Compounds for the treatment of proliferative disorders

ABSTRACT

The invention relates to compounds of structural formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof, wherein R a , R b , and R 2  are defined herein. These compounds inhibit tubulin polymerization and/or target vasculature and are useful for treating proliferative disorders, such as cancer.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/702,237, filed Jul. 25, 2005, U.S. Provisional Application60/749,418, filed Dec. 12, 2005, and U.S. Provisional Application60/780,488, filed Mar. 8, 2006 which are incorporated by referenceherein in their entirety.

FIELD OF THE INVENTION

This invention relates to biologically active chemical compounds, namely[1,2,3]triazole derivatives that may be used for treating or preventingproliferative disorders.

BACKGROUND OF THE INVENTION

Many chemotherapeutic methods are now available to be used in thetreatment of cancer. One of the most successful methods is the use ofanti-mitotic agents which interfere with the assembly or disassembly ofmicrotubules. Since microtubule assemble and disassemble is necessaryfor mitosis, inhibition of either the assembly or disassembly ofmicrotubules interferes with cell proliferation. Thus, compounds thatinhibit the assembly of microtubule are useful in treating diseases orconditions which are caused or exasperated by rapid or abnormal cellproliferation, such as cancer. Several anti-mitotic agents have hadconsiderable clinical success. For example, the following vincaalkaloids which inhibit microtubule assembly have proved clinicallysuccessful: Vincristine has been successfully used to treathematological malignancies and non-small-cell lung carcinoma;Vinblastine has been successfully used to treat hematologicalmalignancies, testicular carcinomas and non-small-cell lung carcinoma;and Vinorelbine has been successfully used to treat hematologicalmalignancies, breast carcinomas and non-small-cell lung carcinoma. Inaddition, taxanes which inhibit microtubule disassemble have also provedto be clinically successful. For example, Paclitaxel has been successfulin treating breast, ovarian and non-small-cell lung carcinomas; andDocetaxel has been successful in treating breast and non-small-cell lungcarcinomas.

Despite these successes, available anti-mitotic agents are inadequatefor a number of reasons. For example, paclitaxel, docetaxel andvincristine are associated with significant neuropathy which can limittheir use in repeat courses of therapy. In addition, both the vincaalkaloids and taxanes are good substrates for the 170 kDa P-glycoprotein(Pgp) efflux pump found in most multi-drug resistant cells. This proteinpumps a drug out of the tumor cells causing the tumor cells to becomeresistant to treatment. Once a patient's cancer has become multi-drugresistant, there is typically little that can be done to halt or retardfurther progression of the disease.

There is therefore still a need for new drugs which overcome one or moreof the aforementioned shortcomings of drugs currently used in thetreatment of cancer. Desirable properties of new anti-cancer drugsinclude a good therapeutic index, efficacy against tumors that arecurrently untreatable or poorly treatable, efficacy against multi-drugresistant tumors and/or reduced side effects.

SUMMARY OF THE INVENTION

This invention meets the above-mentioned needs by providing certain[1,2,3]triazole derivatives that inhibit tubulin polymerization.Compounds of the invention are also capable of vascular targeting, inparticular, blocking, occluding, or otherwise disrupting blood flow inneovasculature. These compounds are particularly useful for treat orprevent proliferative disorders, such as cancer.

In one embodiment, the invention relates to compounds of formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(a) or R_(b) is —H and the other is an optionally        substituted aryl or an optionally substituted heteroaryl. In one        aspect of this embodiment, R_(a) is not acridinyl; and    -   R₂ is an optionally substituted aryl or an optionally        substituted heteroaryl.

In one embodiment, the invention relates to compounds of formula (IA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein one of R_(a) or R_(b) is —H and the        other is an optionally substituted aryl or an optionally        substituted heteroaryl;    -   R^(x) is (R^(aa))_(m), —R^(aa)—C(O)(CH₂)_(n)C(O)OH,        —C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or        —(R^(aa))_(q)C(O)(Y₁);    -   R^(y) is —H or lower alkyl;    -   R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a        haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an        alkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro,        an alkyl ester, or hydroxyl;    -   R₇, for each occurrence, is independently —H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R^(aa) is an amino acid residue or an amino acid residue analog;    -   Y is CH₂, O, or NH;    -   R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁;    -   Alk is an optionally substituted alkylene;    -   Het is an optionally substituted heteroalkyl;    -   Y₁ is a water soluble polymer with a molecular weight less than        60,000 daltons;    -   n is 1, 2, 3, or 4;    -   m is an integer from 1 to 10; and    -   q is 0 or 1.    -   In another embodiment, in the compounds represented by formula        (IA), neither R_(a) or R_(b) is acridinyl.

In one embodiment, the invention relates to compounds of formula (IB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein one of R_(a) or R_(b) is —H and the        other is an optionally substituted aryl or an optionally        substituted heteroaryl;    -   R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a        haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an        alkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro,        an alkyl ester, or hydroxyl;    -   R₇, for each occurrence, is independently —H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl.        In another embodiment, in the compounds represented by formula        (IB), neither R_(a) or R_(b) is acridinyl.

Compounds of the invention or pharmaceutically acceptable salts,solvates, clathrates, or prodrugs thereof are potent antimitotic agentswhich inhibiting tubulin polymerization, and thus can inhibitmicrotubule growth. In order for cells to undergo mitosis, microtubulesmust be able to assemble and disassemble, in a process known as dynamicinstability. Thus, in one embodiment, the compounds of the invention canbe used to inhibit tubulin polymerization in a cell by contacting thecell with an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of the invention can be used to inhibittubulin polymerization in a subject by administering to the subject aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof.

Compounds of the invention or pharmaceutically acceptable salts,solvates, clathrates, or prodrugs thereof are vascular targeting agentswhich can be used to block, occlude, or otherwise disrupt blood flow inneovasculature, and thus lead to destruction of vasculature. Thus in oneembodiment, compounds of the invention can be used to block, occlude, orotherwise disrupt blood flow in neovasculature by contacting theneovasculature with an effective amount of a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of the invention can be used to block,occlude, or otherwise disrupt blood flow in neovasculature of a subjectby administering to the subject an effective amount of a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

Since the compounds of the invention, disrupt mitosis by inhibitingtubulin polymerization, they are particularly useful in treating orpreventing proliferative disorders, such as cancer. Therefore, in oneembodiment, compounds of the invention or pharmaceutically acceptablesalts, solvates, clathrates, or prodrugs thereof can be used to treat orprevent a proliferative disorder in a subject by administering to thesubject an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

All of the methods of this invention may be practice with a compound ofthe invention alone, or in combination with other agents, such as otheranti-cancer agents.

As will be described in detail below, compounds of the inventionovercome or ameliorated some of the limitation of known anti-mitoticagents. In particular, compounds of the invention are cytotoxic inmultidrug resistant cells, and thus may be useful for treating cancersthat have become resistant to other therapies.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term “aryl” means a monocyclic orpolycyclic-aromatic ring or ring radical comprising carbon and hydrogenatoms. Typically, aryl groups have about 6 to about 14 carbon atom ringmembers. Examples of suitable aryl groups include, but are not limitedto, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, andnaphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or more substituents (including without limitationalkyl (preferably, lower alkyl or alkyl substituted with one or morehalo), hydroxy, alkoxy (preferably, lower alkoxy), alkylsulfanyl(preferably, lower alkylsulfanyl), cyano, halo, amino, and nitro. Incertain embodiments, the aryl group is a monocyclic ring, wherein thering comprises 6 carbon atoms.

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon typically having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyland n-decyl; while saturated branched alkyls include isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl,2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethyl pentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkylgroups included in compounds of this invention may be optionallysubstituted with one or more substituents. Examples of substituentsinclude, but are not limited to, amino, alkylamino, alkoxy,alkylsulfanyl, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl,aryloxy, arylsulfanyl, arylamino, carbocyclyl, carbocyclyloxy,carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylthio, and the like. In addition, anycarbon in the alkyl segment may be substituted with oxygen (═O), sulfur(═S), or nitrogen (═NR³², wherein R³² is —H, an alkyl, acetyl, oraralkyl). Lower alkyls are typically preferred for the compounds of thisinvention.

The term alkylene refers to an alkyl group or a cycloalkyl group thathas two points of attachment to two moieties (e.g., {—CH₂—}, —{CH₂CH₂—},

etc., wherein the brackets indicate the points of attachment). Alkylenegroups may be optionally substituted with one or more substituents.

An aralkyl group refers to an aryl group that is attached to anothermoiety via an alkylene linker. Aralkyl groups can be optionallysubstituted with one or more substituents.

The term “alkoxy,” as used herein, refers to an alkyl group which islinked to another moiety though an oxygen atom. Preferred alkoxy groupsare methoxy, ethoxy, isopropoxy, n-propoxy, and the like. The alkylportion of an alkoxy group can be optionally substituted with one ormore substituents.

The term “alkylsulfanyl,” as used herein, refers to an alkyl group whichis linked to another moiety though a divalent sulfur atom. Preferred,alkylsulfanyl groups are methylsulfanyl and ethylsulfanyl. The alkylportion of an alkylsulfanyl group can be optionally substituted with oneor more substituents.

The term “arylsulfanyl,” as used herein, refers to an aryl group whichis linked to another moiety though a divalent sulfur atom (e.g.,phenylsulfanyl). The aryl portion of an arylsulfanyl groups can beoptionally substituted with one or more substituents.

The term “alkyl ester” or “alkoxycarbonyl,” as used herein, refers to agroup represented by the formula —C(O)OR₃₂, wherein R₃₂ is an alkylgroup. A “lower alkyl ester” or a “lower alkoxycarbonyl” is a grouprepresented by the formula —C(O)OR₃₂, wherein R₃₂ is a lower alkylgroup.

The term “heteroalkyl,” as used herein, refers to an alkyl group whichhas one or more carbons in the alkyl chain replaced with an —O—, —S— or—NR₃₃—, wherein R₃₃ is H or a lower alkyl. Heteroalkyl groups can beoptionally substituted with one or more substituents.

The term “alkylamino,” as used herein, refers to an amino group in whichone hydrogen atom attached to the nitrogen has been replaced by an alkylgroup. The term “dialkylamino,” as used herein, refers to an amino groupin which two hydrogen atoms attached to the nitrogen have been replacedby alkyl groups, in which the alkyl groups can be the same or different.The alkyl portion of alkylamino groups and dialkylamino groups can beoptionally substituted with one or more substituents.

As used herein, the term “alkenyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups can be optionally substitutedwith one or more substituents.

As used herein, the term “alkynyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at lease one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and the like. Alkynyl groupscan be optionally substituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical typically having from 3 to 14 carbon atoms.Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly,decahydronaphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and thelike. Cycloalkyl groups can be optionally substituted with one or moresubstituents.

As used herein, the term “cycloalkenyl” means a cyclic non-aromaticalkenyl radical having at least one carbon-carbon double bond in thecyclic system and typically having from 3 to 14 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl and the like. Cycloalkenyl groups can be optionallysubstituted with one or more substituents.

As used herein, the term “heterocycle” or “heterocyclyl” means amonocyclic or polycyclic heterocyclic ring (typically having 3- to14-members) which is either a saturated ring or an unsaturatednon-aromatic ring. A 3-membered heterocycle can contain from 1 to 3heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 toabout 8 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The heterocyclyl may be attached via anyheteroatom or carbon atom. Representative heterocyclyls includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, 4H-pyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. A heteroatom may be substituted with a protecting group knownto those of ordinary skill in the art, for example, the hydrogen on anitrogen may be substituted with a tert-butoxycarbonyl group.Furthermore, the heterocyclyl may be optionally substituted with one ormore substituents (including without limitation a halo, an alkyl, ahaloalkyl, or aryl). Only stable isomers of such substitutedheterocyclic groups are contemplated in this definition.

As used herein, the term “heteroaryl” means a monocyclic or polycyclicaromatic ring (or radical thereof) comprising carbon atom ring membersand one or more heteroatom ring members (such as, for example, oxygen,sulfur or nitrogen). Typically, the heteroaromatic ring has from 5 toabout 14 ring members in which at least 1 ring member is a heteroatomselected from oxygen, sulfur and nitrogen. In another embodiment, theheteroaromatic ring is a 5 or 6 membered ring and may contain from 1 toabout 4 heteroatoms. In another embodiment, the heteroaromatic ringsystem has a 7 to 14 ring members and may contain from 1 to about 7heteroatoms. Representative heteroaryls include pyridyl, furyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl,indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl,imidazopyridinyl, isothiazolyl, tetrazolyl, benzo[1,3]dioxolyl,2,3-dihydro-benzo[1,4]dioxinyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl,tetrahydroindolyl, azaindolyl, imidazopyridyl, qunizaolinyl, purinyl,pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl or benzo[b]thienyl and thelike. Heteroaryl groups may be optionally substituted with one or moresubstituents

A heteroaralkyl group refers to a heteroaryl group that is attached toanother moiety via an alkylene linker. Heteroaralkyl groups can besubstituted or unsubstituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means an alkyl group in which oneor more —H is replaced with a halo group. Examples of haloalkyl groupsinclude —CF₃, —CHF₂, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, —CHICH₃, andthe like.

As used herein, the term “haloalkoxy” means an alkoxy group in which oneor more —H is replaced with a halo group. Examples of haloalkoxy groupsinclude —OCF₃ and —OCHF₂.

An “amino acid” is compound represented by NH₂—CH(R₂₁)—COOH, wherein R₂₁is H or an amino acid sidechain. A “naturally-occurring amino acid” isfound in nature. Examples include alanine, valine, leucine, isoleucine,aspartic acid, glutamic acid, serine, threonine, glutamine, asparagine,arginine, lysine, ornithine, proline, hydroxyproline, phenylalanine,tyrosine, tryptophan, cysteine, methionine and histidine. Examples ofnaturally occurring amino acid sidechains include methyl (alanine),isopropyl (valine), sec-butyl (isoleucine), —CH₂CH(CH₃)₂ (leucine),benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), —CH₂OH (serine),—CH(OH)CH₃ (threonine), —CH₂-3-indoyl (tryptophan), —CH₂COOH (asparticacid), —CH₂CH₂COOH (glutamic acid), —CH₂C(O)NH₂ (asparagine),—CH₂CH₂C(O)NH₂ (glutamine), —CH₂SH, (cysteine), —CH₂CH₂SCH₃(methionine), —(CH₂)₄NH₂ (lysine), —(CH₂)₃NH₂ (ornithine),—(CH₂)₃NHC(═NH)NH₂ (arginine) and —CH₂-3-imidazoyl (histidine).

The side-chains of alanine, valine, leucine and isoleucine arealiphatic, i.e., contain only carbon and hydrogen, and are each referredto herein as “the aliphatic side-chain of a naturally occurring aminoacid.”

The side-chains of other naturally-occurring amino acids comprise aheteroatom-containing functional group, e.g., an alcohol (serine,tyrosine, hydroxyproline and threonine), an amine (lysine, ornithine,histidine and arginine), a thiol (cysteine) or a carboxylic acid(aspartic acid and glutamic acid). When the heteroatom-containingfunctional group is modified to include a protecting group, theside-chain is referred to as the “protected sidechain” of an amino acid.

The selection of a suitable protecting group depends upon the functionalgroup being protected, the conditions to which the protecting group isbeing exposed and to other functional groups which may be present in themolecule. Suitable protecting groups for the functional groups discussedabove are described in Greene and Wuts, “Protective Groups in OrganicSynthesis”, John Wiley & Sons (1991), the entire teachings of which areincorporated into this application by reference. The skilled artisan canselect, using no more than routine experimentation, suitable protectinggroups for use in the disclosed synthesis, including protecting groupsother than those described below, as well as conditions for applying andremoving the protecting groups.

Examples of suitable alcohol protecting groups include benzyl, allyl,trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like. Benzylis a preferred alcohol protecting group.

Examples of suitable amino protecting groups include benzyloxycarbonyl,tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxycarbonyl(Fmoc). Tert-butoxycarbonyl is a preferred amine protecting group.

Examples of suitable carboxylic acid protecting groups includetert-butyl, Fmoc, methyl, methoxylmethyl, trimethylsilyl,benzyloxymethyl, tert-butyldimethylsilyl and the like. Tert-butyl is apreferred carboxylic acid protecting group.

Examples of suitable thiol protecting groups include S-benzyl,S-tert-butyl, S-acetyl, S-methoxymethyl and the like.

The terms “bioisostere” and “bioisosteric replacement” have the samemeanings as those generally recognized in the art. Bioisosteres areatoms, ions, or molecules in which the peripheral layers of electronscan be considered substantially identical. The term bioisostere isusually used to mean a portion of an overall molecule, as opposed to theentire molecule itself. Bioisosteric replacement involves using onebioisostere to replace another with the expectation of maintaining orslightly modifying the biological activity of the first bioisostere. Thebioisosteres in this case are thus atoms or groups of atoms havingsimilar size, shape and electron density. Preferred bioisosteres ofesters, amides or carboxylic acids are compounds containing two sitesfor hydrogen bond acceptance. In one embodiment, the ester, amide orcarboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring,such as an optionally substituted 1H-imidazolyl, an optionallysubstituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionallysubstituted [1,2,4]oxadiazolyl.

As used herein, the terms “subject”, “patient” and “animal”, are usedinterchangeably and include, but are not limited to, a cow, monkey,horse, sheep, pig, mini pig, chicken, turkey, quail, cat, dog, mouse,rat, rabbit, guinea pig and human. The preferred subject, patient oranimal is a human.

As used herein, the term “lower” refers to a group having up to fourcarbon atoms. For example, a “lower alkyl” refers to an alkyl radicalhaving from 1 to 4 carbon atoms, and a “lower alkenyl” or “loweralkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4carbon atoms, respectively. A lower alkoxy or a lower alkylsulfanylrefers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms.Lower substituents are typically preferred.

Where a particular substituent, such as an alkyl substituent, occursmultiple times in a given structure or moiety, the identity of thesubstituent is independent in each case and may be the same as ordifferent from other occurrences of that substituent in the structure ormoiety. Furthermore, individual substituents in the specific embodimentsand exemplary compounds of this invention are preferred in combinationwith other such substituents in the compounds of this invention, even ifsuch individual substituents are not expressly noted as being preferredor not expressly shown in combination with other substituents.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino,dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groupsinclude any substituent which will form a stable compound of theinvention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl,alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkylinclude an optionally substituted alkyl, an optionally substitutedalkoxy, an optionally substituted alkylsulfanyl, an optionallysubstituted alkylamino, an optionally substituted dialkylamino, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, anoptionally substituted haloalkyl, —C(O)NR₃₄R₃₅, —NR₃₆C(O)R₃₇, halo,—OR₃₆, cyano, nitro, haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅, —SR₃₆, —C(O)OR₃₆,—OC(O)R₃₆, —NR₃₆C(O)NR₃₄R₃₅, —NR₃₆C(N—R₃₈)NR₃₄R₃₅, —OC(O)NR₃₄R₃₅,—NR₃₆C(O)OR₃₇, —OP(O)(OR₃₆)₂, —SP(O)(OR₃₆)₂, —OS(O)₂(OR₃₆),—S(O)_(p)R₃₆, or —S(O)_(p)NR₃₄R₃₅, wherein R₃₄ and R₃₅, for eachoccurrence are, independently, H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₃₄and R₃₅ taken together with the nitrogen to which they are attached isan optionally substituted heterocyclyl or an optionally substitutedheteroaryl; R₃₆ and R₃₇ for each occurrence are, independently, H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; and R₃₅ is H, an optionally substituted alkyl,—C(O)R₃₆, —C(O)OR₃₆, or an optionally substituted aralkyl.

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₃₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned bythis invention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject). Typically, such compounds arestable at a temperature of 40° C. or less, in the absence of excessivemoisture, for at least one week. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as, without limitation, carboxy,hydroxy, and amino moieties) also include protected derivatives thereof.“Protected derivatives” are those compounds in which a reactive site orsites are blocked with one or more protecting groups. Suitableprotecting groups for carboxy moieties include benzyl, tert-butyl, andthe like. Suitable protecting groups for amino and amido groups includeacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for hydroxy include benzyl, trimethyl silyl (TMS) andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the entire teachings of which are incorporated herein by reference.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of any one of formulas (I) through (XIX),(IA) through (XIA), (XVIIA) through (XIXA), (IB) through (XIB), (XVIIB)through (XIXB), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof and also include protectedderivatives thereof.

As used herein, the term “amino acid residue” refers to what is left ofan amino acid (losing a H⁺ from the nitrogenous side, an OH⁻ from thecarboxylic side, or a H⁺ from the nitrogenous side and an OH⁻ from thecarboxylic side) in the formation of a peptide bond(s). An “amino acidanalog” includes D or L amino acids having the following formula:NH₂—CHR—C(O)OH, wherein R is an optionally substituted alkyl group, anoptionally substituted heteroalkyl group, an optionally substitutedaromatic group, or an optionally substituted heteroaromatic group, andwherein R does not correspond to the side chain of a naturally-occurringamino acid. An “amino acid residue analog” refers to what is left of anamino acid analog (losing a H⁺ from the nitrogenous side, an OH⁻ fromthe carboxylic side, or a H⁺ from the nitrogenous side and an OH⁻ fromthe carboxylic side) in the formation of a peptide bond(s).

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, but they may have activity intheir unreacted forms. Examples of prodrugs contemplated in thisinvention include, but are not limited to, analogs or derivatives ofcompounds of any one of formulas (I) through (XIX), (IA) through (XIA),(XVIIA) through (XIXA), (IB) through (XIB), (XVIIB) through (XIXB), orTable 1, that comprise biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. Other examples of prodrugs include derivatives ofcompounds of any one of formulas (I) through (XIX), (IA) through (XIA),(XVIIA) through (XIXA), (IB) through (XIB), (XVIIB) through (XIXB), orTable 1, that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs cantypically be prepared using well-known methods, such as those describedby 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178,949-982 (Manfred E. Wolff ed., 5^(th) ed), the entire teachings of whichare incorporated herein by reference.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines. Examples of biohydrolyzable phosphate analoguesinclude —OP(O)(OR₁₂)₂ and —SP(O)(OR₁₂)₂, wherein R₁₂ for each occurrenceis independently H or a lower alkyl.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from an acid and a basic group of one of the compounds of any oneof formulas (I) through (XIX), (IA) through (XIA), (XVIIA) through(XIXA), (IB) through (XIB), (XVIIB) through (XIXB), or Table 1.Illustrative salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of any one of formulas (I) through (XIX), (IA) through (XIA),(XVIIA) through (XIXA), (IB) through (XIB), (XVIIB) through (XIXB), orTable 1, having an acidic functional group, such as a carboxylic acidfunctional group, and a pharmaceutically acceptable inorganic or organicbase. Suitable bases include, but are not limited to, hydroxides ofalkali metals such as sodium, potassium, and lithium; hydroxides ofalkaline earth metal such as calcium and magnesium; hydroxides of othermetals, such as aluminum and zinc; ammonia, and organic amines, such asunsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine;diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkylamines), such as mono-, bis-, or tris-(2-hydroxyethyl)-amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of formulas (I) through (XIX), (IA)through (XIA), (XVIIA) through (XIXA), (IB) through (XIB), (XVIIB)through (XIXB), or Table 1, having a basic functional group, such as anamino functional group, and a pharmaceutically acceptable inorganic ororganic acid. Suitable acids include, but are not limited to, hydrogensulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid,hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid,isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconicacid, glucaronic acid, saccharic acid, formic acid, benzoic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone or more molecules of a compound of any one of formulas (I) through(XIX), (IA) through (XIA), (XVIIA) through (XIXA), (IB) through (XIB),(XVIIB) through (XIXB), or Table 1. The term solvate includes hydrates(e.g., hemi-hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate,and the like).

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

Inhibition of tubulin polymerization can be determined by any methodknown to those skilled in the art, such as the method described hereinin Example 4 or 5. In addition the amount of a tubulin polymerizationinhibitor that inhibits 50% of tubulin polymerization that occurs in theabsence of the inhibitor (i.e., the IC₅₀) can be determined bypre-incubating purified tubulin with various amounts of an inhibitor for15 minutes at 37° C. The mixture is then cooled to room temperature andGTP is added to induce tubulin polymerization. The polymerization can bemonitored in a spectrophotometer at 350 nm. A typical reaction mixtures(0.25 mL) contains 1.5 mg/mL tubulin, 0.6 mg/mL microtubule-associatedproteins (MAPs), 0.5 mM GTP, 0.5 mIM MgCl.sub.2, 4% DMSO and 0.1M4-morpholineethanesulfonate buffer (MES, pH 6.4).

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.,diabetic retinopathy or other retinopathies), choroidalneovascularisation (e.g., macular degeneration), cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, and desmoidtumors.

Smooth muscle cell proliferation includes hyperproliferation of cells inthe vasculature, for example, intimal smooth muscle cell hyperplasia,restenosis and vascular occlusion, particularly stenosis followingbiologically- or mechanically-mediated vascular injury, e.g., vascularinjury associated with angioplasty. Moreover, intimal smooth muscle cellhyperplasia can include hyperplasia in smooth muscle other than thevasculature, e.g., bile duct blockage, bronchial airways of the lung inpatients with asthma, in the kidneys of patients with renal interstitialfibrosis, and the like.

Non-cancerous proliferative disorders also include hyperproliferation ofcells in the skin such as psoriasis and its varied clinical forms,Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferativevariants of disorders of keratinization (e.g., actinic keratosis, senilekeratosis), scleroderma, and the like.

In a preferred embodiment, the proliferative disorder is cancer. Cancersthat can be treated or prevented by the methods of the present inventioninclude, but are not limited to human sarcomas and carcinomas, e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavychain disease.

Other examples of leukemias include acute and/or chronic leukemias,e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine)cell line), large granular lymphocytic leukemia, and lymphoblasticleukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplifiedby the CEM, Jurkat, and HSB-2 (acute), YAC-1(murine) cell lines),T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia(e.g., as exemplified by the SB (acute) cell line), and B-lymphocyticleukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and Tlymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia,myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte)cell line), and myelogenous leukemia (e.g., as exemplified by theK562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia;monocytic leukemia (e.g., as exemplified by the THP-1(acute) cell line);myelomonocytic leukemia; Naegeli-type myeloid leukemia; andnonlymphocytic leukemia. Other examples of leukemias are described inChapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed.,Williams & Williams (1992) and Section 36 of Holland Frie CancerMedicine 5th Ed., Bast et al. Eds., B.C. Decker Inc. (2000). The entireteachings of the preceding references are incorporated herein byreference.

In one embodiment, the compounds of the invention are believed to beparticularly effective in treating subject with hematologicalmalignancies (e.g., Hodgkin's disease, Non-Hodgkin lymphoma, acutelymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenousleukemia, chronic lymphocytic leukemia, and multiple myeloma). Inanother embodiment, the compounds of the invention are believed to beparticularly useful in treating solid tumors.

In one embodiment, the compounds of the invention are particularlyeffective at treating subjects whose cancer has become “multi-drugresistant”. A cancer which initially responded to an anti-cancer drugbecomes resistant to the anti-cancer drug when the anti-cancer drug isno longer effective in treating the subject with the cancer. Forexample, many tumors will initially respond to treatment with ananti-cancer drug by decreasing in size or even going into remission,only to develop resistance to the drug. Drug resistant tumors arecharacterized by a resumption of their growth and/or reappearance afterhaving seemingly gone into remission, despite the administration ofincreased dosages of the anti-cancer drug. Cancers that have developedresistance to two or more anti-cancer drugs are said to be “multi-drugresistant”. For example, it is common for cancers to become resistant tothree or more anti-cancer agents, often five or more anti-cancer agentsand at times ten or more anti-cancer agents.

In another embodiment the compound of the invention are particularlyuseful in treating solid tumors.

An “effective amount” is the quantity of compound in which a beneficialoutcome is achieved when the compound is administered to a subject oralternatively, the quantity of compound that possess a desired activityin vivo or in vitro. In the case of proliferative disorders, abeneficial clinical outcome includes reduction in the extent or severityof the symptoms associated with the disease or disorder and/or anincrease in the longevity and/or quality of life of the subject comparedwith the absence of the treatment. For example, for a subject withcancer, a “beneficial clinical outcome” includes a reduction in tumormass, a reduction in the rate of tumor growth, a reduction inmetastasis, a reduction in the severity of the symptoms associated withthe cancer and/or an increase in the longevity of the subject comparedwith the absence of the treatment. The precise amount of compoundadministered to a subject will depend on the type and severity of thedisease or condition and on the characteristics of the subject, such asgeneral health, age, sex, body weight and tolerance to drugs. It willalso depend on the degree, severity and type of proliferative disorder.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. Effective amounts of the disclosedcompounds typically range between about 1 mg/mm² per day and about 10grams/mm² per day, and preferably between 10 mg/mm² per day and about 1gram/mm².

In one embodiment, compounds of the invention are vascular targetingagents. In one aspect, compounds of the invention are effective forblocking, occluding, or otherwise disrupting blood flow in“neovasculature.” In one aspect, the invention provides a noveltreatment for diseases involving the growth of new blood vessels(“neovasculature”), including, but not limited to: cancer; infectiousdiseases; autoimmune disorders; benign tumors, e.g. hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas;artheroscleric plaques; ocular angiogenic diseases, e.g., diabeticretinopathy, retinopathy of prematurity, macular degeneration, cornealgraft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome,choroidal neovascularization, uvietis and Pterygia (abnormal bloodvessel growth) of the eye; rheumatoid arthritis; psoriasis; warts;allergic dermatitis; blistering disease; Karposi sarcoma; delayed woundhealing; endometriosis; uterine bleeding; ovarian cysts; ovarianhyperstimulation; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; vascular malformations; DiGeorge syndrome; HHT; transplantarteriopathy; restinosis; obesity; myocardial angiogenesis; coronarycollaterals; cerebral collaterals; arteriovenous malformations; ischemiclimb angiogenesis; primary pulmonary hypertension; asthma; nasal polyps;inflammatory bowel disease; periodontal disease; ascites; peritonealadhesions; Osler-Webber Syndrome; plaque neovascularization;telangiectasia; hemophiliac joints; synovitis; osteomyelitis; osteophyteformation; angiofibroma; fibromuscular dysplasia; wound granulation;Crohn's disease; and atherosclerosis.

Vascular targeting can be demonstrated by any method known to thoseskilled in the art, such as the method described herein in Example 7.

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric,diastereomeric, and geometric isomeric mixtures. In some cases, oneenantiomer, diastereomer, or geometric isomer will possess superioractivity or an improved toxicity or kinetic profile compared to others.In those cases, such enantiomers, diastereomers, and geometric isomersof a compound of this invention are preferred.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to all chiral centersin the molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of any one of formulas(I) through (XIX), (IA) through (XIA), (XVIIA) through (XIXA), (IB)through (XIB), (XVIIB) through (XIXB), or Table 1.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are typically administeredin isolated form or as the isolated form in a pharmaceuticalcomposition. As used herein, “isolated” means that the compounds of theinvention are separated from other components of either (a) a naturalsource, such as a plant or cell, preferably bacterial culture, or (b) asynthetic organic chemical reaction mixture. Preferably, viaconventional techniques, the compounds of the invention are purified. Asused herein, “purified” means that when isolated, the isolate containsat least 95%, preferably at least 98%, of a single compound of theinvention by weight of the isolate.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

Specific Embodiments

The invention relates to compounds and pharmaceutical compositions thatare useful for inhibiting tubulin polymerization and are particularlyuseful in treating or preventing proliferative disorders, such ascancer. The invention also relates to compounds and pharmaceuticalcompositions that are useful as vascular targeting agents, particularly,in blocking, occluding, or otherwise disrupting blood flow inneovasculature.

In one embodiment, the invention relates to compounds of formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein R_(a), R_(b), and R₂ are defined as        above. In another embodiment, in the compounds represented by        formula (I), R_(a) is not acridinyl.

In another embodiment, the invention relates to compounds of formula(II):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(c) or R_(d) is —H and the other is

-   -   ring A is optionally substituted; and    -   X₁, X₂, X₃, X₄, and X₅ are each, independently, N or CR₁₄,        provided that at least two of X₁, X₂, X₃, X₄, and X₅ are CR₁₄;        and    -   R₁₄ is —H or a substituent.

In another embodiment, the invention relates to compounds of formula(III):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(e) or R_(f) is —H and the other is

-   -   R₃, R₄, R₅, and R₆ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OSS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R₉ is —H, halo, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁;    -   R₇, R₈, R₁₀, R₁₁, and p are defined as above.

In another embodiment, the invention relates to compounds represented byformulae (IIa) through (IIe):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R_(e) and R_(f) are defined as above;    -   R₁₉ is —H, halo, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁; and    -   R₇, R₈, R₁₀, R₁₁, and p are defined as above.

In another embodiment, the invention relates to compounds of formula(IV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(g) or R_(h) is —H and the other is

-   -   X₁, X₂, X₃, and X₄ are each, independently, N or CR₁₄, provided        that at least two of X₁, X₂, X₃, X₄, and X₅ are CR₁₄;    -   Ring B is optionally substituted with one to three substituents;    -   Ring C is optionally substituted with one or two substituents;        and    -   R₁₄ is defined as above.

In another embodiment, the invention relates to compounds of formula(V):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(i) or R_(j) is —H and the other is

-   -   R₆ and R₉ are defined as above; and    -   R₁₃ is —H, an alkyl, an alkoxy, a halo, nitro, cyano, —OH, —NH₂,        an alkyl amino, or a dialkyl amino.

In another embodiment, the invention relates to compounds of formulae:

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein R_(i), R_(j), and R₁₉ are defined as        above.

In another embodiment, the invention relates to compounds of formula(XIX):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₆ or R₈₇ is —H and the other is

-   -   Ring D is optionally substituted one to three substituents;    -   X₁, X₂, X₃, X₄, and X₅ are each, independently, N or CR₁₄,        provided that at least two of X₁, X₂, X₃, X₄, and X₅ are CR₁₄;        and    -   X, R₁₄, R₁₅, and R₁₆ are defined as above.

In another embodiment, the invention relates to compounds of formula(VI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₇₂ or R₇₃ is —H and the other is

-   -   Ring D, X, R₆, R₉, R₁₅ and R₁₆ are defined as above.

In another embodiment, the invention relates to compounds of formula(VII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(k) or R_(l) is —H and the other is

-   -   one of rings E or F is substituted with three or four        substituents and the other is substituted with one or more        substituents. In another embodiment, in the compounds        represented by formula (VII), when R_(k) is —H, then Ring E is        not 4-aminophenyl.

In another embodiment, the invention relates to compounds of formula(VIII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(m) or R_(n) is —H and the other is

-   -   R₃, R₄, R₅, R₆ and R₉ are defined as above.

In another embodiment, the invention relates to compounds of formula(IX):

-   -   a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(o) or R_(p) is —H and the other is

-   -   R₁₇ are each, independently, halo, an optionally substituted        alkyl, an optionally substituted alkenyl, an optionally        substituted alkynyl, an optionally substituted cycloalkyl, an        optionally substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, cyano, nitro, guanadino, a        haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,        —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,        —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,        —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and    -   R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and p are defined as above.

In another embodiment, the invention relates to compounds of formula(X):

-   -   a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(q) or R_(f) is —H and the other is

-   -   R₁₈ are each, independently, halo, an optionally substituted        alkyl, an optionally substituted alkenyl, an optionally        substituted alkynyl, an optionally substituted cycloalkyl, an        optionally substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, cyano, nitro, guanadino, a        haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,        —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,        —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,        —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and    -   R₃, R₅, R₆, R₇, R₈, R₆, R₁₀, R₁₁ and p are defined as above.

In another embodiment, the invention relates to compounds of formula(XI):

-   -   a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(s) or R_(t) is —H and the other is

-   -   R₃, R₄, R₅, R₆, R₉, and R₁₈ are defined as above.

In another embodiment, the invention relates to compounds of formula(XII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(u) or R_(v) is —H and the other is

-   -   ring G is substituted with three to five substituents;    -   X₆, X₇, X₈, X₉, and X₁₀ are each, independently, N or CR₁₄,        provided that at least one of X₆, X₇, X₈, X₉, or X₁₀ is N and at        least two of X₆, X₇, X₈, X₉, and X₁₀ are CR₁₄; and    -   R₁₄ is defined as above.

In another embodiment, the invention relates to compounds of formula(XIV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₇₆ or R₇₇ is —H and the other is

-   -   X₆, X₇, X₈, X₉, and X₁₀ are each, independently, N or CR₁₄,        provided that at least one of X₆, X₇, X₈, X₉, or X₁₀ is N and at        least two of X₆, X₇, X₈, X₉, and X₁₀ are CR₁₄;    -   Ring B is optionally substituted with one to three substituents;    -   Ring C is optionally substituted with one or two substituents;        and    -   R₁₄ is defined as above.

In another embodiment, the invention relates to compounds of formula(XV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₇₈ or R₇₉ is —H and the other is

-   -   ring G is optionally substituted with one to five substituents;    -   ring H is optionally substituted with one to three substituents;    -   ring I is optionally substituted with one or two substituents;    -   X₁₁, and X₁₂ are each, independently, N or CR₁₄, provided that        at least one X₉, or X₁₀ is N; and    -   R₁₄ is defined as above.

In another embodiment, the invention relates to compounds of formula(XVI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein;    -   one of R₈₀ or R₈₁ is —H and the other is

-   -   X₁₁, X₁₂, R₃, R₄, and R₅ are defined as above.

In another embodiment, the invention relates to compounds of formula(XVII):

-   -   a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₂ or R₈₃ is —H and the other is

-   -   ring J is substituted with three or four substituents;    -   X₁, X₂, X₃, X₄, and X₅ are each, independently, N or CR₁₄,        provided that at least two of X₁, X₂, X₃, X₄, and X₅ are CR₁₄;        and    -   R₁₄ is defined as above.

In another embodiment, the invention relates to compounds of formula(XVIII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₄ or R₈₅ is —H and the other is

-   -   R₃, R₄, R₅, R₆ and R₉ are defined as above.

In one embodiment, the invention relates to compounds of formula (IA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein one of R_(a) or R_(b) is —H and the        other is an optionally substituted aryl or an optionally        substituted heteroaryl;    -   R^(x) is (R^(aa))_(m), —R^(aa)—C(O)(CH₂)_(n)C(O)OH,        —C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or        —(R^(aa))_(q)C(O)(Y₁);    -   R^(y) is —H or lower alkyl;    -   R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a        haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an        alkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro,        an alkyl ester, or hydroxyl;    -   R₇, for each occurrence, is independently —H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R^(aa) is an amino acid residue or an amino acid residue analog;    -   Y is CH₂, O, or NH;    -   R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁;    -   Alk is an optionally substituted alkylene;    -   Het is an optionally substituted heteroalkyl;    -   Y₁ is a water soluble polymer with a molecular weight less than        60,000 daltons;    -   n is 1, 2, 3, or 4;    -   m is an integer from 1 to 10; and    -   q is 0 or 1.    -   In another embodiment, in the compounds represented by formula        (IA), neither R_(a) or R_(b) is acridinyl.

In another embodiment, the invention relates to compounds of formula(IIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(c) or R_(d) is —H and the other is

-   -   ring A is optionally substituted; and    -   R^(x), R^(y), and R_(w) are defined as above.

In another embodiment, the invention relates to compounds of formula(IIIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(e) or R_(f) is —H and the other is

-   -   R₃, R₄, and R₅ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁; and    -   R^(x), R^(y), R^(w), R₇, R₈, R₁₀, R₁₁, and p are defined as        above.

In another embodiment, the invention relates to compounds of formula(IVA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(g) or R_(h) is —H and the other is

-   -   Ring B is optionally substituted with one to three substituents;    -   Ring C is optionally substituted with one or two substituents;        and    -   R^(x), R^(y), and R^(w) are defined as above.

In another embodiment, the invention relates to compounds of formula(VA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(i) or R_(j) is —H and the other is

-   -   R^(x), R^(y), and R^(w) are defined as above; and    -   R₁₃ is —H, an alkyl, an alkoxy, a halo, nitro, cyano, —OH, —NH₂,        an alkyl amino, or a dialkyl amino.

In another embodiment, the invention relates to compounds of formula(VIIA):

-   -   (VIIA)    -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(k) or R_(l) is —H and the other is

-   -   Ring E is substituted with one or more substituents.

In another embodiment, the invention relates to compounds of formula(XIXA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₆ or R₈₇ is —H and the other is

-   -   Ring D is optionally substituted one to three substituents; and    -   R^(x), R^(y), R^(w), X, R₁₅, and R₁₆ are defined as above.

In another embodiment, the invention relates to compounds of formula(VIIIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein    -   one of R_(m) or R_(n) is —H and the other is

-   -   R^(x), R^(y), R^(w) R₆ and R₉ are defined as above.

In another embodiment, the invention relates to compounds of formula(IXA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(o) or R_(p) is —H and the other is

-   -   R₁₇ are each, independently, halo, an optionally substituted        alkyl, an optionally substituted alkenyl, an optionally        substituted alkynyl, an optionally substituted cycloalkyl, an        optionally substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, cyano, nitro, guanadino, a        haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,        —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,        —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,        —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and    -   R₄, R₅, R^(x), R^(y), R^(w), R₇, R₈, R₁₀, R₁₁ and p are defined        as above.

In another embodiment, the invention relates to compounds of formula(XA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(q) or R_(r) is —H and the other is

-   -   R₁₈ are each, independently, halo, an optionally substituted        alkyl, an optionally substituted alkenyl, an optionally        substituted alkynyl, an optionally substituted cycloalkyl, an        optionally substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, cyano, nitro, guanadino, a        haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,        —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,        —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,        —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and    -   R₃, R₅, R^(x), R^(y), R^(w), R₇, R₈, R₉, R₁₀, R₁₁ and p are        defined as above.

In another embodiment, the invention relates to compounds of formula(XIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(s) or R_(t) is —H and the other is

-   -   R₃, R₄, R₅, R^(x), R^(y), R^(w) and R₁₈ are defined as above.

In another embodiment, the invention relates to compounds of formula(XVIIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₂ or R₈₃ is —H and the other is

-   -   ring J is substituted with three or four substituents; and    -   R^(x), R^(y), R^(w), and R₁₄ are defined as above.

In another embodiment, the invention relates to compounds of formula(XVIIIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₄ or R₈₅ is —H and the other is

-   -   R₃, R₄, R₅, R^(x), R^(y), and R^(w) are defined as above.

In one embodiment, the invention relates to compounds of formula (IB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein    -   one of R_(a) or R_(b) is —H and the other is an optionally        substituted aryl or an optionally substituted heteroaryl;    -   R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a        haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an        alkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro,        an alkyl ester, or hydroxyl;    -   R₇, for each occurrence, is independently —H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl.    -   In another embodiment, in the compounds represented by formula        (IB), neither R_(a) or R_(b) is acridinyl.

In another embodiment, the invention relates to compounds of formula(IIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(c) or R_(d) is —H and the other is

-   -   ring A is optionally substituted; and    -   R^(x), R^(y), and R^(w) are defined as above.

In another embodiment, the invention relates to compounds of formula(IIIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(e) or R_(f) is —H and the other is

-   -   R₃, R₄, R₅, and R₆ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁; and    -   R^(x), R^(y), R^(w), R₇, R₈, R₁₀, R₁₁, and p are defined as        above.

In another embodiment, the invention relates to compounds of formula(IVB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(g) or R_(h) is —H and the other is

-   -   Ring B is optionally substituted with one to three substituents;    -   Ring C is optionally substituted with one or two substituents;        and    -   R^(x), R^(y), and R^(w) are defined as above.

In another embodiment, the invention relates to compounds of formula(VB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(i) or R_(j) is —H and the other is

-   -   R^(x), R^(y), and R^(w) are defined as above; and    -   R₁₃ is —H, an alkyl, an alkoxy, a halo, nitro, cyano, —OH, —NH₂,        an alkyl amino, or a dialkyl amino.

In another embodiment, the invention relates to compounds of formula(VIIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(k) or R_(l) is —H and the other is

-   -   one of rings E or F is substituted with three or four        substituents and the other is substituted with one or more        substituents.

In another embodiment, the invention relates to compounds of formula(XIXB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₆ or R₈₇ is —H and the other is

-   -   Ring D is optionally substituted one to three substituents; and    -   R^(x), R^(y), R^(w), X, R₁₅, and R₁₆ are defined as above.

In another embodiment, the invention relates to compounds of formula(VIIIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(m) or R_(n) is —H and the other is

-   -   R^(x), R^(y), R^(w) R₆ and R_(g) are defined as above.

In another embodiment, the invention relates to compounds of formula(IXB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(o) or R_(p) is —H and the other is

-   -   R₁₇ are each, independently, halo, an optionally substituted        alkyl, an optionally substituted alkenyl, an optionally        substituted alkynyl, an optionally substituted cycloalkyl, an        optionally substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, cyano, nitro, guanadino, a        haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,        —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,        —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,        —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and    -   R₄, R₅, R^(x), R^(y), R^(w), R₇, R₈, R₁₀, R₁₁ and p are defined        as above.

In another embodiment, the invention relates to compounds of formula(XB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(q) or R_(r) is —H and the other is

-   -   R₁₈ are each, independently, halo, an optionally substituted        alkyl, an optionally substituted alkenyl, an optionally        substituted alkynyl, an optionally substituted cycloalkyl, an        optionally substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, cyano, nitro, guanadino, a        haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,        —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,        —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,        —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and    -   R₃, R₅, R^(x), R^(y), R^(w), R₇, R₈, R₉, R₁₀, R₁₁ and p are        defined as above.

In another embodiment, the invention relates to compounds of formula(XIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(s) or R_(t) is —H and the other is

-   -   R₃, R₄, R₅, R^(x), R^(y), R^(w) and R₁₈ are defined as above.

In another embodiment, the invention relates to compounds of formula(XVIIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₂ or R₈₃ is —H and the other is

-   -   ring J is substituted with three or four substituents; and    -   R^(x), R^(y), R^(w), and R₁₄ are defined as above.

In another embodiment, the invention relates to compounds of formula(XVIIIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R₈₄ or R₈₅ is —H and the other is

-   -   R₃, R₄, R₅, R^(x), R^(y), and R^(w) are defined as above.

In some embodiments, R_(a) and R₂ in formula (I) are each independentlya substituted or unsubstituted phenyl. In some embodiments, R_(b) and R₂in formula (I) are each independently a substituted or unsubstitutedphenyl.

In some embodiments, R_(a) in formula (I), (IA), or (IB) is —H. In someembodiments, R_(b) in formula (I), (IA), or (IB) is —H.

In some embodiments, R₃ of formula (III), (IIIA), (IIIB), (IIa), (IIb),(IIc), (IId), (IIe), (VIII), (VIIIA), (VIIIB), (X), (XA), (XB), (XI),(XIA), (XIB), (XVI), (XVIII), (VIIIA), or (XVIIIB) is a lower alkyl,lower alkoxy, lower alkylsulfanyl, —OH, —SH, —NH₂, halo, lower dialkylamino, lower alkyl amino, nitro, cyano, pyridinyl, carboxy, loweralkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂, —OC(O)R₁₂,—OS(O)₂(OR₁₂), tetrazolyl, 1-methyl-tetrazolyl, —NHC(O)R₁₂, or—NHC(O)CH(R₂₁)NH₂, wherein R₁₂ for each occurrence is independently, —Hor a lower alkyl; and R₂₁ is H or an amino acid sidechain. In someembodiments, R₃ of formula (III), (IIIA), (IIIB), (IIa), (IIb), (IIc),(IId), (IIe), (VIII), (VIIIA), (VIIIB), (X), (XA), (XB), (XI), (XIA),(XIB), (XVI), (XVIII), (VIIIA), or (XVIIIB) is methyl, ethyl, ormethoxy; preferably, R₃ is methoxy.

In some embodiments, R₄ of formula (III), (IIIA), (IIIB), (IIa), (IIb),(IIc), (IId), (IIe), (VIII), (VIIIA), (VIIIB), (X), (XA), (XB), (XI),(XIA), (XIB), (XVI), (XVIII), (VIIIA), or (XVIIIB) is a lower alkyl,lower alkoxy, lower alkylsulfanyl, —OH, —SH, —NH₂, halo, lower dialkylamino, lower alkyl amino, nitro, cyano, pyridinyl, carboxy, loweralkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂, —OC(O)R₁₂,—OS(O)₂(OR₁₂), tetrazolyl, 1-methyl-tetrazolyl, —NHC(O)R₁₂, or—NHC(O)CH(R₂₁)NH₂, wherein R₁₂ for each occurrence is independently, —Hor a lower alkyl; and R₂₁ is H or an amino acid sidechain. In someembodiments, R₄ of formula (III), (IIIA), (IIIB), (IIa), (IIb), (IIc),(IId), (IIe), (VIII), (VIIIA), (VIIIB), (X), (XA), (XB), (XI), (XIA),(XIB), (XVI), (XVIII), (VIIIA), or (XVIIIB) is methyl, ethyl, ormethoxy; preferably, R₄ is methoxy.

In some embodiments, R₅ of formula (III), (IIIA), (IIIB), (IIa), (IIb),(IIc), (IId), (IIe), (VIII), (VIIIA), (VIIIB), (X), (XA), (XB), (XI),(XIA), (XIB), (XVI), (XVIII), (VIIIA), or (XVIIIB) is a lower alkyl,lower alkoxy, lower alkylsulfanyl, —OH, —SH, —NH₂, halo, lower dialkylamino, lower alkyl amino, nitro, cyano, pyridinyl, carboxy, loweralkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂, —OC(O)R₁₂,—OS(O)₂(OR₁₂), tetrazolyl, 1-methyl-tetrazolyl, —NHC(O)R₁₂, or—NHC(O)CH(R₂₁)NH₂, wherein R₁₂ for each occurrence is independently, —Hor a lower alkyl; and R₂₁ is H or an amino acid sidechain. In someembodiments, R₅ of formula (III), (IIIA), (IIb), (IIc), (IId), (IIe),(VIII), (VIIIA), (VIIIB), (X), (XA), (XB), (XI), (XIA), (XIB), (XVI),(XVIII), (VIIIA), or (XVIIIB) is methyl, ethyl, or methoxy; preferably,R₃ is methoxy.

In some embodiments, R₆ of formula (III), (V), (VI), (VIII), (IX), (X),(XI), or (XVIII) is a lower alkyl, lower alkoxy, lower alkylsulfanyl,—OH, —SH, —NH₂, halo, lower dialkyl amino, lower alkyl amino, nitro,cyano, pyridinyl, carboxy, lower alkoxycarbonyl, oxazolyl,—SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂, —OC(O)R₁₂, —OS(O)₂(OR₁₂), tetrazolyl,1-methyl-tetrazolyl, —NHC(O)R₁₂, or —NHC(O)CH(R₂₁)NH₂, wherein R₁₂ foreach occurrence is independently, —H or a lower alkyl; and R₂₁ is H oran amino acid sidechain. In some embodiments, R₆ of formula (III), (V),(VI), (VIII), (IX), (X), (XI), or (XVIII) is methyl, ethyl, or methoxy;preferably, R₃ is methoxy. In some embodiments, R₆ of formula (III),(V), (VI), (VIII), (IX), (X), (XI), or (XVIII) is a lower alkyl, loweralkoxy, lower alkylsulfanyl, —OH, —SH, —NH₂, halo, lower dialkyl amino,lower alkyl amino, nitro, pyridinyl, carboxy, lower alkoxycarbonyl,oxazolyl, —SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂, —OC(O)R₁₂, —OS(O)₂(OR₁₂),tetrazolyl, 1-methyl-tetrazolyl, or —NHC(O)R₁₂; preferably, R₆ ismethoxy, dimethyl amino, methyl amino, hydroxy, —NHC(O)CH(R₂₁)NH₂,—OS(O)₂OR₁₂, —SP(O)(OR₁₂)₂, or —OP(O)(OR₁₂)₂; more preferably, R₃ ismethoxy.

In some embodiments, R₃, R₄, and R₅ of formula (III), (IIIA), (IIIB),(IIa), (IIb), (IIc), (IId), (IIe), (VIII), (VIIIA), (VIIIB), (X), (XA),(XB), (XI), (XIA), (XIB), (XVI), (XVIII), (VIIIA), or (XVIIIB) are each,independently, a lower alkyl, lower alkoxy, lower alkylsulfanyl, —OH,—SH, —NH₂, halo, lower dialkyl amino, lower alkyl amino, nitro, cyano,pyridinyl, carboxy, lower alkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂,—OP(O)(OR₁₂)₂, —OC(O)R₁₂, —OS(O)₂(OR₁₂), tetrazolyl,1-methyl-tetrazolyl, —NHC(O)R₁₂, or —NHC(O)CH(R₂₁)NH₂, wherein R₁₂ foreach occurrence is independently, —H or a lower alkyl; and R₂₁ is H oran amino acid sidechain. In some embodiments, R₃, R₄, and R₅ of formula(III), (IIIA), (IIIB), (IIa), (IIb), (IIc), (IId), (IIe), (VIII),(VIIIA), (VIIIB), (X), (XA), (XB), (XI), (XIA), (XIB), (XVI), (XVIII),(VIIIA), or (XVIIIB) are each, independently, methyl, ethyl, or methoxy;preferably, R₃, R₄, and R₅ are each methoxy.

In some embodiments, R₃, R₄, R₅, and R₆ of formula (III), (VIII), (XI),or (XVIII) are each, independently, a lower alkyl, lower alkoxy, loweralkylsulfanyl, —OH, —SH, —NH₂, halo, lower dialkyl amino, lower alkylamino, nitro, cyano, pyridinyl, carboxy, lower alkoxycarbonyl, oxazolyl,—SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂, —OC(O)R₁₂, —OS(O)₂(OR₁₂), tetrazolyl,1-methyl-tetrazolyl, —NHC(O)R₁₂, or —NHC(O)CH(R₂₁)NH₂, wherein R₁₂ foreach occurrence is independently, —H or a lower alkyl; and R₂₁ is H oran amino acid sidechain. In some embodiments, R₃, R₄, R₅, and R₆ offormula (III), (VIII), (XI), or (XVIII) are each, independently, methyl,ethyl, or methoxy; preferably, R₃, R₄, R₅ and R₆ are methoxy. In someembodiments, R₃, R₄, and R₅ of formula (III), (VIII), (XI), or (XVIII)are each, independently, methyl, ethyl, or methoxy, and R₆ of formula(III), (VIII), (XI), or (XVIII) is a lower alkyl, lower alkoxy, loweralkylsulfanyl, —OH, —SH, —NH₂, halo, lower dialkyl amino, lower alkylamino, nitro, pyridinyl, carboxy, lower alkoxycarbonyl, oxazolyl,—SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂, —OC(O)R₁₂, —OS(O)₂(OR₁₂), tetrazolyl,1-methyl-tetrazolyl, or —NHC(O)R₁₂; preferably, R₆ is methoxy, dimethylamino, methyl amino, hydroxy, —NHC(O)CH(R₂₁)NH₂, —OS(O)₂OR₁₂,—SP(O)(OR₁₂)₂, or —OP(O)(OR₁₂)₂; preferably, R₃, R₄, R₅ and R₆ aremethoxy.

In some embodiments, R₄, R₅, and R₆ of formula (IX) are each,independently, a lower alkyl, lower alkoxy, lower alkylsulfanyl, —OH,—SH, —NH₂, halo, lower dialkyl amino, lower alkyl amino, nitro, cyano,pyridinyl, carboxy, lower alkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂,—OP(O)(OR₁₂)₂, —OC(O)R₁₂, —OS(O)₂(OR₁₂), tetrazolyl,1-methyl-tetrazolyl, —NHC(O)R₁₂, or —NHC(O)CH(R₂₁)NH₂, wherein R₁₂ foreach occurrence is independently, —H or a lower alkyl; and R₂₁ is H oran amino acid sidechain. In some embodiments, R₄, R₅, and R₆ of formula(IX) are each, independently, methyl, ethyl, or methoxy; preferably, R₄,R₅ and R₆ are methoxy. In some embodiments, R₄ and R₅ of formula (IX)are each, independently, methyl, ethyl, or methoxy, and R₆ of formula(IX) is a lower alkyl, lower alkoxy, lower alkylsulfanyl, —OH, —SH,—NH₂, halo, lower dialkyl amino, lower alkyl amino, nitro, pyridinyl,carboxy, lower alkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂,—OC(O)R₁₂, —OS(O)₂(OR₁₂), tetrazolyl, 1-methyl-tetrazolyl, or—NHC(O)R₁₂; preferably, R₆ is methoxy, dimethyl amino, methyl amino,hydroxy, —NHC(O)CH(R₂₁)NH₂, —OS(O)₂OR₁₂, —SP(O)(OR₁₂)₂, or—OP(O)(OR₁₂)₂; preferably, R₄, R₅ and R₆ are methoxy.

In some embodiments, R₃, R₅, and R₆ of formula (X) are each,independently, a lower alkyl, lower alkoxy, lower alkylsulfanyl, —OH,—SH, —NH₂, halo, lower dialkyl amino, lower alkyl amino, nitro, cyano,pyridinyl, carboxy, lower alkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂,—OP(O)(OR₁₂)₂, —OC(O)R₁₂, —OS(O)₂(OR₁₂), tetrazolyl,1-methyl-tetrazolyl, —NHC(O)R₁₂, or —NHC(O)CH(R₂₁)NH₂, wherein R₁₂ foreach occurrence is independently, —H or a lower alkyl; and R₂₁ is H oran amino acid sidechain. In some embodiments, R₃, R₅, and R₆ of formula(X) are each, independently, methyl, ethyl, or methoxy; preferably, R₃,R₅ and R₆ are methoxy. In some embodiments, R₃ and R₅ of formula (X) areeach, independently, methyl, ethyl, or methoxy, and R₆ of formula (X) isa lower alkyl, lower alkoxy, lower alkylsulfanyl, —OH, —SH, —NH₂, halo,lower dialkyl amino, lower alkyl amino, nitro, pyridinyl, carboxy, loweralkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂, —OP(O)(OR₁₂)₂, —OC(O)R₁₂,—OS(O)₂(OR₁₂), tetrazolyl, 1-methyl-tetrazolyl, or —NHC(O)R₁₂;preferably, R₆ is methoxy, dimethyl amino, methyl amino, hydroxy,—NHC(O)CH(R₂₁)NH₂, —OS(O)₂OR₁₂, —SP(O)(OR₁₂)₂, or —OP(O)(OR₁₂)₂;preferably, R₃, R₅ and R₆ are methoxy.

In some embodiments, R₉ of formula (III), (V), (VI), (VIII), (VIIIA),(VIIIB), (IX), (X), (XI), or (XVIII) is —H, halo, —OH, —SH, —NH₂,carboxy, —OP(O)(OR₁₂)₂, —SP(O)(OR₁₂)₂, —NHC(O)R₁₂, —NHC(O)CH(R₂₁)NH₂,—OS(O)₂(OR₁₂), lower alkoxycarbonyl, or lower alkoxy; preferably, R₉ is—H, amino, hydroxy, —NHC(O)CH(R₂₁)NH₂, or —OP(O)(OR₁₂)₂.

In some embodiments, R₁₃ of formula (V), (VA), (VB), (IVa), (IVb),(IVc), (IVd) or (IVe) is —H or a lower alkoxy.

In some embodiments, ring A of formula (II), (IIA), or (IIB) isoptionally substituted with one to five substituents independentlyselected from the group consisting of an optionally substituted alkyl,an optionally substituted alkoxy, an optionally substitutedalkylsulfanyl, an optionally substituted alkylamino, an optionallysubstituted dialkylamino, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, an optionally substituted haloalkyl, —C(O)NR₃₄R₃₅,—NR₃₆C(O)R₃₇, halo, —OR₃₆, cyano, nitro, haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅,—SR₃₆, —C(O)OR₃₆, —OC(O)R₃₆, —NR₃₆C(O)NR₃₄R₃₅, —NR₃₆C(N—R₃₈)NR₃₄R₃₅,—OC(O)NR₃₄R₃₅, —NR₃₆C(O)OR₃₇, —OP(O)(OR₃₆)₂, —SP(O)(OR₃₆)₂,—OS(O)₂(OR₃₆), —S(O)_(p)R₃₆, or —S(O)_(p)NR₃₄R₃₅, wherein R₃₄ and R₃₅,for each occurrence are, independently, H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₃₄and R₃₅ taken together with the nitrogen to which they are attached isan optionally substituted heterocyclyl or an optionally substitutedheteroaryl; R₃₆ and R₃₇ for each occurrence are, independently, H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; and R₃₈ is H, an optionally substituted alkyl,—C(O)R₃₆, —C(O)OR₃₆, or an optionally substituted aralkyl.

In some embodiments, ring B of formula (IV), (IVA), or (IVB) isoptionally substituted with one to three substituents independentlyselected from the group consisting of an optionally substituted alkyl,an optionally substituted alkoxy, an optionally substitutedalkylsulfanyl, an optionally substituted alkylamino, an optionallysubstituted dialkylamino, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, an optionally substituted haloalkyl, —C(O)NR₃₄R₃₅,—NR₃₆C(O)R₃₇, halo, —OR₃₆, cyano, nitro, haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅,—SR₃₆, —C(O)OR₃₆, —OC(O)R₃₆, —NR₃₆C(O)NR₃₄R₃₅, —NR₃₆C(N—R₃₈)NR₃₄R₃₅,—OC(O)NR₃₄R₃₅, —NR₃₆C(O)OR₃₇, —OP(O)(OR₃₆)₂, —SP(O)(OR₃₆)₂,—OS(O)₂(OR₃₆), —S(O)_(p)R₃₆, or —S(O)_(p)NR₃₄R₃₅.

In some embodiments, ring C of formula (IV), (IVA), or (IVB) isoptionally substituted with one or two substituents independentlyselected from the group consisting of an optionally substituted alkyl,an optionally substituted alkoxy, an optionally substitutedalkylsulfanyl, an optionally substituted alkylamino, an optionallysubstituted dialkylamino, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, an optionally substituted haloalkyl, —C(O)NR₃₄R₃₅,—NR₃₆C(O)R₃₇, halo, —OR₃₆, cyano, nitro, haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅,—SR₃₆, —C(O)OR₃₆, —OC(O)R₃₆, —NR₃₆C(O)NR₃₄R₃₅, —NR₃₆C(N—R₃₈)NR₃₄R₃₅,—OC(O)NR₃₄R₃₅, —NR₃₆C(O)OR₃₇, —OP(O)(OR₃₆)₂, —SP(O)(OR₃₆)₂,—OS(O)₂(OR₃₆), —S(O)_(p)R₃₆, —S(O)_(p)NR₃₄R₃₅, ═O, ═S, ═NR₃₈.

In some embodiments, ring D of formula (XIX), (XIXA), (XIXB), or (VI)are optionally substituted with one to three substituents independentlyselected from the group consisting of an optionally substituted alkyl,an optionally substituted alkoxy, an optionally substitutedalkylsulfanyl, an optionally substituted alkylamino, an optionallysubstituted dialkylamino, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, an optionally substituted haloalkyl, —C(O)NR₃₄R₃₅,—NR₃₆C(O)R₃₇, halo, —OR₃₆, cyano, nitro, haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅,—SR₃₆, —C(O)OR₃₆, —OC(O)R₃₆, —NR₃₆C(O)NR₃₄R₃₅, —NR₃₆C(N—R₃₈)NR₃₄R₃₅,—OC(O)NR₃₄R₃₅, —NR₃₆C(O)OR₃₇, —OP(O)(OR₃₆)₂, —SP(O)(OR₃₆)₂,—OS(O)₂(OR₃₆), —S(O)_(p)R₃₆, or —S(O)_(p)NR₃₄R₃₅. Preferably, ring D offormula (XIX) or (VI) is optionally substituted with one to fivesubstituents independently selected from the group consisting of halo,an optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, aheteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and R₁₅ and R₁₆ areindependently selected from the group consisting of —H or a halo, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, aheteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁.

In some embodiments, ring E and/or ring F of formula (VII) areoptionally substituted with one to five substituents independentlyselected from the group consisting of an optionally substituted alkyl,an optionally substituted alkoxy, an optionally substitutedalkylsulfanyl, an optionally substituted alkylamino, an optionallysubstituted dialkylamino, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, an optionally substituted haloalkyl, —C(O)NR₃₄R₃₅,—NR₃₆C(O)R₃₇, halo, —OR₃₆, cyano, nitro, haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅,—SR₃₆, —C(O)OR₃₆, —OC(O)R₃₆, —NR₃₆C(O)NR₃₄R₃₅, —NR₃₆C(N—R₃₈)NR₃₄R₃₅,—OC(O)NR₃₄R₃₅, —NR₃₆C(O)OR₃₇, —OP(O)(OR₃₆)₂, —SP(O)(OR₃₆)₂,—OS(O)₂(OR₃₆), —S(O)_(p)R₃₆, or —S(O)_(p)NR₃₄R₃₅.

In some embodiments, ring E of formula (VIIA) or (VIIB) is optionallysubstituted with one to five substituents independently selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkoxy, an optionally substituted alkylsulfanyl, anoptionally substituted alkylamino, an optionally substituteddialkylamino, an optionally substituted alkenyl; an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,an optionally substituted haloalkyl, —C(O)NR₃₄R₃₅, —NR₃₆C(O)R₃₇, halo,—OR₃₆, cyano, nitro, haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅, —SR₃₆, —C(O)OR₃₆,—OC(O)R₃₆, —NR₃₆C(O)NR₃₄R₃₅, —NR₃₆C(N—R₃₈)NR₃₄R₃₅, —OC(O)NR₃₄R₃₅,—NR₃₆C(O)OR₃₇, —OP(O)(OR₃₆)₂, —SP(O)(OR₃₆)₂, —OS(O)₂(OR₃₆),—S(O)_(p)R₃₆, or —S(O)_(p)NR₃₄R₃₅.

In some embodiments, R₁₄, for each occurrence, is independently selectedfrom the group consisting of —H, an optionally substituted alkyl, anoptionally substituted alkoxy, an optionally substituted alkylsulfanyl,an optionally substituted alkylamino, an optionally substituteddialkylamino, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,an optionally substituted haloalkyl, —C(O)NR₃₄R₃₅, —NR₃₆C(O)R₃₇, halo,—OR₃₆, cyano, nitro, haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅, —SR₃₆, —C(O)OR₃₆,—OC(O)R₃₆, —NR₃₆C(O)NR₃₄R₃₅, —NR₃₆C(N—R₃₈)NR₃₄R₃₅, —OC(O)NR₃₄R₃₅,—NR₃₆C(O)OR₃₇, —OP(O)(OR₃₆)₂, —SP(O)(OR₃₆)₂, —OS(O)₂(OR₃₆),—S(O)_(p)R₃₆, or —S(O)_(p)NR₃₄R₃₅. Preferably, R₁₄ is —H, a lower alkyl,a lower alkoxy, a lower alkyl sulfanyl, a amino, a lower alkyl amino, alower dialkyl amino, hydroxy, —NHC(O)CH(R₂₁)NH₂, —OP(O)(OR₁₂)₂, halo,—SH, carboxy, —SP(O)(OR₁₂)₂, —NHC(O)R₁₂, —OS(O)₂(OR₁₂), loweralkoxycarbonyl, or lower alkoxy; preferably, R₁₄ is —H, amino, hydroxy,—NHC(O)CH(R₂₁)NH₂, or —OP(O)(OR₁₂)₂.

In some embodiments, in the compounds represented by formula (VIIA) orVIIIB), R₆ is lower alkyl, lower alkoxy, lower alkylsulfanyl, —OH, —SH,—NH₂, halo, lower dialkyl amino, lower alkyl amino, nitro, cyano,pyridinyl, carboxy, lower alkoxycarbonyl, oxazolyl, —SP(O)(OR₁₂)₂,—OP(O)(OR₁₂)₂, —OC(O)R₁₂, —OS(O)₂(OR₁₂), tetrazolyl,1-methyl-tetrazolyl, —NHC(O)R₁₂, or —NHC(O)CH(R₂₁)NH₂, wherein R₁₂ foreach occurrence is independently, —H or a lower alkyl; and R₂₁ is H oran amino acid sidechain; and R₉ is —H, halo, —OH, —SH, —NH₂, carboxy,—OP(O)(OR₁₂)₂, —SP(O)(OR₁₂)₂, —NHC(O)R₁₂, —NHC(O)CH(R₂₁)NH₂,—OS(O)₂(OR₁₂), lower alkoxycarbonyl, or lower alkoxy.

In some embodiments, in the compounds represented by formula (IXA) or(IXB), R₄, R₅, and R₁₇ are each, independently, a lower alkyl, a loweralkoxy, or —OH.

In some embodiments, in the compounds represented by formula (XA) or(XB), R₃, R₅, and R₁₈ are each, independently, a lower alkyl, a loweralkoxy, or —OH.

In some embodiments, in the compounds represented by formula (XIA) or(XIB), R₃, R₄, R₅, and R₁₈ are each, independently, a lower alkyl, alower alkoxy, or —OH.

In one embodiment, in formula (VI), (XIX), (XIXA), or (XIXB), X is NR₂₀;Ring D is unsubstituted; R₂₀ is —H or a lower alkyl; and R₁₅ and R₁₆ are—H.

In one embodiment, in formula (VI), (XIX), (XIXA), or (XIXB), X is O;Ring D is unsubstituted; and R₁₅ and R₁₆ are —H.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), R^(x) is R^(aa), —C(O)YR^(z), or—C(O)NH—R^(aa). In one aspect, R^(x) is R^(aa). In another aspect, R^(x)is —C(O)YR^(z). R^(aa), R^(z), and Y are defined as for formula (IA).

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), R^(x) is R^(aa) and R^(aa) is defined asfor formula (IA). In one aspect, R^(aa) is glycine, serine, alanine,phenylalanine, leucine, or methionine.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), R^(x) is R^(aa) and R^(y) is —H, whereinR^(aa) is defined as for formula (IA). In one aspect, R^(aa) is glycine,alanine, valine, leucine, isoleucine, serine, threonine, cysteine,methionine, phenylalanine, tyrosine, tryptophan, aspartic acid,asparagine, glutamic acid, glutamine, arginine, histidine, lysine, orproline. In another aspect, R^(aa) is glycine, serine, alanine,phenylalanine, leucine, or methionine.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), R^(x) is R^(aa) and R^(aa) is a D-aminoacid residue or a D-amino acid residue analog. In one aspect, R^(aa) isD-alanine, D-valine, D-leucine, D-isoleucine, D-serine, D-threonine,D-cysteine, D-methionine, D-phenylalanine, D-tyrosine, D-tryptophan,D-aspartic acid, D-asparagine, D-glutamic acid, D-glutamine, D-arginine,D-histidine, D-lysine, or D-proline.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), R^(x) is R^(aa) and R^(aa) is an L-aminoacid residue or an L-amino acid residue analog. In one aspect, R^(aa) isL-alanine, L-valine, L-leucine, L-isoleucine, L-serine, L-threonine,L-cysteine, L-methionine, L-phenylalanine, L-tyrosine, L-tryptophan,L-aspartic acid, L-asparagine, L-glutamic acid, L-glutamine, L-arginine,L-histidine, L-lysine, or L-proline.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), R^(x) is —C(O)YR^(z) and Y and R^(z) aredefined as for formula (IA). In one aspect, Y is CH₂. In another aspect,Y is O. In another aspect, Y is NH. In one aspect, R^(z) is Y₁ and Y₁ isdefined as for formula (IA). In another aspect, R^(z) is Alk-NH₂. Inanother aspect, R^(z) is Alk-C(O)OH. In another aspect, R^(z) is Het.Alk and Het and defined as for formula (IA).

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), m is 1, 2 or 3.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), Y₁ is PEG, HPMAcopolymer-methacryloyl-Gly-Phe-Leu-Gly-ethylenediamine, or HPMAcopolymer-methacryloyl-Gly-Phe-Leu-Gly-OH. In one aspect, Y₁ is PEG.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), R^(y) is —H.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), R^(y) is a lower alkyl.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), Y₁ has a molecular weight greater than20,000 daltons. In one aspect, Y₁ has a molecular weight of less than40,000 daltons, but greater than 25,000 daltons.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XIA),(XVIIA), (XVIIIA) or (XIXA), Alk is an optionally substituted loweralkylene.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIIA), (VIIIA), (IXA), (XA), (XVIIA),(XVIIIA) or (XIXA), Het is an optionally substituted lower heteroalkyl.

In some embodiments, in the compounds represented by formula (IIIA), R₃,R₄, and R₅ are each methoxy. In one aspect, R^(x) is R^(aa). In anotheraspect, R^(x) is (R^(aa))_(m). In another aspect, R^(x) is—R^(aa)—C(O)(CH₂)_(n)C(O)OH. In another aspect, R^(x) is—C(O)(CH₂)_(n)C(O)OH. In another aspect, R^(x) is —C(O)YR^(z). Inanother aspect, R^(x) is —C(O)NH—R^(aa). In another aspect, R^(x) is—(R^(aa))_(q)C(O)(Y₁). R^(aa), Y, R^(z), Y₁, m, n, and q are defined asfor formula (IA).

In some embodiments, in the compounds represented by formula (IIIA), R₃,R₄, and R₅ are each methoxy. In one aspect, R^(x) is R^(aa) and R^(w) isalkoxy. In another aspect, R^(x) is R^(aa) and R^(y) is —H. In anotheraspect, R^(x) is R^(aa), R^(w) is alkoxy, and R^(y) is —H. In anotheraspect, R^(x) is R^(aa), R^(w) is alkoxy, and R^(y) is —H. In anotheraspect, R^(x) is R^(aa), R^(w) is methoxy, and R^(y) is —H. R^(aa) isdefined as for formula (IA).

In some embodiments, in the compounds represented by formula (IIIB), R₃,R₄, and R₅ are each methoxy; and R^(w) is alkoxy. In one aspect, R^(w)is methoxy.

In some embodiments, in the compounds represented by formula (IA or B),(IIA or B), (IIIA or B), (IVA or B), (VA or B), (VIIA or B), (VIIIA orB), (IXA or B), (XA or B), (XIA or B), (XVIIA or B), (XVIIIA or B), or(XIXA or B), Fr is alkoxy. In one aspect, R^(w) is methoxy.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   1-(3,4,5-trimethoxy-phenyl)-5-(4-bromo-phenyl)-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(naphthylen-2-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(4-iodo-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(4-bromo-phenyl)-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-(4-bromo-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-hydroxy-phenyl)-5-(4-hyoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-iodo-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-fluoro-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-nitro-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-amino-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4′-methoxy-biphenyl-4-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-[4-(pyridin-3-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-[4-(pyridin-4-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-[4-(pyridin-2-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(quinolin-7-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(pyridine-4-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(isoquinolin-7-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(1-methyl-1H-indol-5-yl)-1H-[1,2,3]triazole;-   1-(benzo[1,3]dioxol-5-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole,-   1-(1-ethyl-1H-indol-6-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-carboxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-carbomethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-[4-(oxazol-2-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-(4-iodo-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-(3-fluoro-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-(4-nitro-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-trimethyl-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-[4-(pyridine-3-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-[4-(pyridine-4-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-[4-(pyridine-2-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-(quinolin-7-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-(pyridine-4-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-(isoquinolin-7-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-triethyl-phenyl)-5-(1H-indol-5-yl)-1H-[1,2,3]triazole;-   1-(benzo[1,3]dioxol-5-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(1-isopropyl-1H-indol-6-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,4-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   O-ethyl-O-{2-methoxy-5-[1-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazol-5-yl]-phenyl}-phosphate;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-isopropyl-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(2,3-dihydro-benzo[1,4]dioxine-6-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-ethyl-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(5-methoxy-pyridine-2-yl)-1H-[1,2,3]triazole;-   1-(4,5,6-trimethoxy-pyridin-2-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,5-dimethoxy-4-carbomethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,5-diacetoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(2-methoxy-pyridine-5-yl)-1H-[1,2,3]triazole;-   1-(1-methyl-5-methoxy-1H-indol-7-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(1-methyl-1H-indol-7-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(Benzo[1,3]dioxol-4-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(2-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   O-ethyl-O-{5-methoxy-2-[1-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazol-5-yl]-phenyl}-phosphate;-   1-(3,4,5-trimethoxy-phenyl)-5-(pyridazin-4-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(pyrimidin-5-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(pyridin-2-yl)-1H-[1,2,3]triazole,    hydrochloric acid salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(2-mercapto-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   S-{2-methoxy-5-[1-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazol-5-yl]-phenyl}-thiophosphate,    disodium salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-acetamido-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-amino-4-methoxy-phenyl)-1H-[1,2,3]triazole,    hydrochloric acid salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(2-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(2-methoxy-pyridin-5-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(5-methoxy-pyridin-2-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-carboxy-4-methoxy-phenyl)-1H-[1,2,3]triazole,    sodium salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-methoxycarbonyl-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-sulfooxy-4-methoxy-phenyl)-1H-[1,2,3]triazole,    sodium salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(2-amino-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-phosphonooxy-4,5-dimethoxy-phenyl)-1H-[1,2,3]triazole,    disodium salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(2-phosphonooxy-4-methoxy-phenyl)-1H-[1,2,3]triazole,    disodium salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-methylsulfanyl-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-phosphonooxy-4-methylsulfanyl-phenyl)-1H-[1,2,3]-triazole,    disodium salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(3-amino-4-methylsulfanyl-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(2,3-dihydro-benzofuran-6-yl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-hydroxy-phenyl)-1H-[1,2,3]triazole,    sodium salt;-   1-(3,4,5-trimethoxy-phenyl)-5-(4-phosphonooxy-phenyl)-1H-[1,2,3]triazole,    disodium salt;-   1-(3,4,5-trimethoxy-phenyl)-5-[4-(tetrazol-5-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-[4-(1-methyl-tetrazol-5-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(1-methyl-1H-indol-5-yl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(pyridazin-4-yl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(pyrimidin-5-yl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(pyridine-3-yl)-1H-[1,2,3]triazole,    hydrochloric acid salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-mercapto-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   S-{2-methoxy-5-[1-(7-methoxy-benzo[1,3]dioxol-5-yl)-1H-[1,2,3]triazol-5-yl]-phenyl}-thiophosphate,    disodium salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-acetamindo-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-amino-4-methoxy-phenyl)-1H-[1,2,3]triazole,    hydrochloric acid salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(2-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(2-methoxy-pyridin-5-yl)-1H-[1,2,3]triazole,-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(5-methoxy-pyridin-2-yl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-carboxy-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-methoxycarbonyl-4-methoxy-phenyl)-1H-[1,2,3]triazole,-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-sulfooxy-4-methoxy-phenyl)-1H-[1,2,3]triazole,    sodium salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(2-amino-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-phosphonyl-4,5-dimethoxy-phenyl)-1H-[1,2,3]triazole,    disodium salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(2-phosphonyl-4-methoxy-phenyl)-1H-[1,2,3]triazole,    sodium salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(4-methylsulfanyl-phenyl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-phosphonyl-4-methylsulfanyl-phenyl)-1H-[1,2,3]triazole,    disodium salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(3-amino-4-methylsulfanyl-phenyl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(2,3-dihydro-benzofuran-6-yl)-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(4-hydroxy-phenyl)-1H-[1,2,3]triazole,    sodium salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(4-phosphonooxy-phenyl)-1H-[1,2,3]triazole,    disodium salt;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-[1H-tetrazol-5-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-[1-methyl-1H-tetrazol-5-yl)-phenyl]-1H-[1,2,3]triazole;-   1-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(1-methyl-1H-indol-5-yl)-1H-[1,2,3]triazole;-   1-(1-methyl-1H-indol-5-yl)-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3-phosphonooxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole,    disodium salt;-   1-[4-(N,N-dimethylamino)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3-amino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole,    hydrochloric acid salt;-   2-hydroxy-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-[1,2,3]triazol-1-yl]-phenylcarbamoyl}-ethyl-ammonium    chloride;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-methyl-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-ethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-ethyl-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-propoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-propyl-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-butoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-butyl-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-bromo-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-chloro-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-fluoro-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(4-nitro-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(3,4-dimethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(3-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,4,5-trimethoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-methyl-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-ethoxy-phenyl)-1H-[1,2,3]triazole,-   1-(2,3,5-trimethoxy-phenyl)-5-(4-ethyl-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-propoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-propyl-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-butoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-butyl-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-bromo-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-chloro-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-fluoro-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(4-nitro-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(3,4-dimethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(3-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(2,3,5-trimethoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-methoxy-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-methyl-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-ethoxy-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-ethyl-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-propoxy-phenyl)-5(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-propyl-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H[1,2,3]triazole;-   1-(4-butoxy-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-butyl-phenyl)-5(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-bromo-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-chloro-phenyl)-5(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-fluoro-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-nitro-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-[4-(N,N-dimethylamino)-phenyl]-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4-dimethoxy-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3-hydroxy-4-methoxy-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4,5-trimethoxy-phenyl)-5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole;-   1-(3,4-trimethoxy-phenyl)-5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(3,4-dimethyl-phenyl)-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(4-chloro-phenyl)-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-propyl-phenyl)-5-phenyl-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(4-methyl-phenyl)-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(4-amino-phenyl)-1H-[1,2,3]triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(4-trifluoromethyl-phenyl)-1H-[1,2,3]-triazole;-   1-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole;-   1-(4-bromo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole;-   or pharmaceutically acceptable salts, solvates, clathrates, or    prodrugs thereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)acetamide    hydrochloride;-   2-amino-3-hydroxy-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)propanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)propanamide;-   2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4-(methylthio)butanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)butanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-phenylpropanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4-methylpentanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(4-methoxyphenyl)propanamide    hydrochloride;-   1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3-methyl-1-oxobutan-2-aminium    chloride;-   1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3-methyl-1-oxopentan-2-aminium    chloride;-   3-hydroxy-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxobutan-2-aminium    chloride;-   3-(4-hydroxyphenyl)-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   2-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2-oxo-1-phenylethanaminium    chloride;-   3-(1H-indol-2-yl)-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   3-(benzofuran-2-yl)-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   3-carboxy-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   4-carboxy-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxobutan-2-aminium    chloride;-   5-amino-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1,5-dioxopentan-2-aminium    chloride;-   4-amino-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1,4-dioxobutan-2-aminium    chloride;-   3-(1H-imidazol-5-yl)-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   6-amino-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxohexan-2-aminium    chloride;-   5-guanidino-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopentan-2-aminium    chloride;-   4-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-4-oxobutanoic    acid;-   5-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-5-oxopentanoic    acid;-   3-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3-oxopropan-1-aminium    chloride;-   N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(2-methoxyethoxy)propanamide;-   3-(2-PEG)-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)butyramide;-   N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(2-(methylamino)ethylamino)propanamide;-   3-PEG-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2-oxoethyl)butyramide;-   4-(2-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2-oxoethylamino)-4-oxobutanoic    acid;-   2-methoxyethyl    2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate;-   PEG-2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate;-   3-amino-4-(2-((R)-5-guanidino-1-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopentan-2-ylamino)-2-oxoethylamino)-4-oxobutanoic    acid; and-   2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)propanamide    hydrochloride;    -   or pharmaceutically acceptable salts, solvates, clathrates, or        prodrugs thereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   4-(3,4,5-trimethoxy-phenyl)-5-(4-bromo-phenyl)-1H-[1,2,3]triazole;-   4-ethyl-5-methoxy-2-(5-(naphthalen-2-yl)-1H-1,2,3-triazol-4-yl)phenol;-   5-(4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   4-ethyl-2-(5-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)-5-methoxyphenol;-   N,N-dimethyl-4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline;-   2-(5-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)-4-ethyl-5-methoxyphenol;-   2-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazol-4-yl)-5-methoxy-4-propylphenol;-   5-(5-(4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)benzene-1,2,3-triol;-   5-(4-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(3-fluoro-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline;-   5-(4′-methoxybiphenyl-4-yl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   3-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)pyridine;-   4-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)pyridine,-   2-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)pyridine;-   7-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)quinoline;-   4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)pyridine;-   7-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)isoquinoline;-   1-methyl-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)-1H-indole;-   4-(benzo[d][1,3]dioxol-5-yl)-5-(4-methoxyphenyl)-1H-1,2,3-triazole;-   1-ethyl-6-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indole;-   4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzoic acid;-   methyl 4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzoate;-   2-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)oxazole;-   5-(4-methoxyphenyl)-4-(3,4,5-triethylphenyl)-1H-1,2,3-triazole;-   5-(4-iodophenyl)-4-(3,4,5-triethylphenyl)-1H-1,2,3-triazole;-   5-(3-fluoro-4-methoxyphenyl)-4-(3,4,5-triethylphenyl)-1H-1,2,3-triazole;-   5-(4-nitrophenyl)-4-(3,4,5-triethylphenyl)-1H-1,2,3-triazole;-   N,N-dimethyl-4-(4-(3,4,5-triethylphenyl)-1H-1,2,3-triazol-5-yl)aniline;-   5-(4-methoxyphenyl)-4-(3,4,5-trimethylphenyl)-1H-1,2,3-triazole;-   3-(4-(4-(3,4,5-triethylphenyl)-1H-1,2,3-triazol-5-yl)phenyl)pyridine;-   4-(4-(4-(3,4,5-triethylphenyl)-1H-1,2,3-triazol-5-yl)phenyl)pyridine;-   2-(4-(4-(3,4,5-triethylphenyl)-1H-1,2,3-triazol-5-yl)phenyl)pyridine;-   7-(4-(3,4,5-triethylphenyl)-1H-1,2,3-triazol-5-yl)quinoline;-   4-(4-(3,4,5-triethylphenyl)-1H-1,2,3-triazol-5-yl)pyridine;-   7-(4-(3,4,5-triethylphenyl)-1H-1,2,3-triazol-5-yl)isoquinoline;-   5-(4-(3,4,5-triethylphenyl)-1H-1,2,3-triazol-5-yl)-1H-indole;-   4-(benzo[d][1,3]dioxol-5-yl)-5-(4-methoxyphenyl)-1H-1,2,3-triazole;-   1-isopropyl-6-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indole;-   5-(4-methoxyphenyl)-4-(2,3,4-trimethoxyphenyl)-1H-1,2,3-triazole;-   2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenol;-   ethyl    2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl    hydrogen phosphate;-   4-ethyl-2-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-5-methoxyphenol;-   5-(4-isopropylphenyl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-ethylphenyl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-methoxy-2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)pyridine;-   6-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-2,3,4-trimethoxypyridine;-   methyl    2,6-dimethoxy-4-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)benzoate;-   5-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1,3-phenylene    diacetate;-   2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)pyridine;-   5-methoxy-7-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1-methyl-1H-indole;-   1-ethyl-7-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indole;-   4-(benzo[d][1,3]dioxol-4-yl)-5-(4-methoxyphenyl)-1H-1,2,3-triazole;-   5-methoxy-2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenol;-   ethyl    5-methoxy-2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl    hydrogen phosphate;-   4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)pyridazine;-   5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)pyrimidine;-   3-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)pyridine    hydrochloride;-   2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzenethiol;-   sodium    S-2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl    phosphorothioate;-   N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)acetamide;-   2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzenaminium    chloride;-   5-methoxy-2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenol;-   2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)pyridine;-   5-methoxy-2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)pyridine;-   sodium    2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzoate;-   methyl    2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzoate;-   sodium    2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl    sulfate;-   5-methoxy-2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline;-   sodium    2,3-dimethoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl    phosphate;-   sodium    5-methoxy-2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl    phosphate;-   5-(4-(methylthio)phenyl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   sodium    2-(methylthio)-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl    phosphate;-   2-(methylthio)-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline;-   5-(2,3-dihydrobenzofuran-6-yl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   sodium    4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenolate;-   monosodium monosodium(II)    mono(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl    phosphate);-   5-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-1H-tetrazole;-   1-methyl-5-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-1H-tetrazole;-   1-methyl-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)-1H-indole;-   4-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)pyridazine;-   5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)pyrimidine;-   3-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)pyridine    hydrochloride;-   2-methoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)benzenethiol;-   sodium    S-2-methoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenyl    phosphorothioate;-   N-(2-methoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenyl)acetamide;-   2-methoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)benzenaminium    chloride;-   5-methoxy-2-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenol;-   2-methoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)pyridine;-   5-methoxy-2-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)pyridine;-   sodium    2-methoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)benzoate;-   methyl    2-methoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)benzoate;-   sodium    2-methoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenyl    sulfate;-   5-methoxy-2-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)aniline;-   sodium    2,3-dimethoxy-5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenyl    phosphate;-   sodium    5-methoxy-2-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenyl    phosphate;-   4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-5-(4-(methylthio)phenyl)-1H-1,2,3-triazole;-   sodium    5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)-2-(methylthio)phenyl    phosphate;-   5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)-2-(methylthio)aniline;-   5-(2,3-dihydrobenzofuran-6-yl)-4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole;-   sodium    4-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenolate;-   sodium    4-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenyl    phosphate;-   5-(4-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenyl)-1H-tetrazole;-   5-(4-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)phenyl)-1-methyl-1H-tetrazole;-   5-(4-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)-1-methyl-1H-indole;-   1-methyl-5-(5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indole;-   monosodium monosodium(II)    mono(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl    phosphate);-   N,N-dimethyl-4-(5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)aniline;-   2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)benzenaminium    chloride;-   3-hydroxy-1-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   5-(4-methoxyphenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-p-tolyl-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-ethoxyphenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-ethylphenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-propoxyphenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-propylphenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-butoxyphenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-butylphenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-bromophenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-chlorophenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-fluorophenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-nitrophenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   N,N-dimethyl-4-(4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline;-   5-(3,4-dimethoxyphenyl)-4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   2-methoxy-5-(4-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenol;-   4-(2,4,5-trimethoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-methoxyphenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-p-tolyl-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-ethoxyphenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-ethylphenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-propoxyphenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-propylphenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-butoxyphenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-butylphenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-bromophenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-chlorophenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-fluorophenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(4-nitrophenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   N,N-dimethyl-4-(4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline;-   5-(3,4-dimethoxyphenyl)-4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   2-methoxy-5-(4-(2,3,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenol;-   4-(2,3,5-trimethoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-methoxyphenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   5-(2,3,4,5-tetramethoxyphenyl)-4-p-tolyl-1H-1,2,3-triazole;-   4-(4-ethoxyphenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-ethylphenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-propoxyphenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-propylphenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-butoxyphenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-butylphenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-bromophenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-chlorophenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-fluorophenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   4-(4-nitrophenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   N,N-dimethyl-4-(5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazol-4-yl)aniline;-   4-(3,4-dimethoxyphenyl)-5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazole;-   2-methoxy-5-(5-(2,3,4,5-tetramethoxyphenyl)-1H-1,2,3-triazol-4-yl)phenol;-   5-(2,3,4,5-tetramethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;-   5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole;-   2-(5-(3,4-dimethylphenyl)-1H-1,2,3-triazol-4-yl)-4-ethyl-5-methoxyphenol;-   2-(5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-4-ethyl-5-methoxyphenol;-   5-methoxy-2-(5-phenyl-1H-1,2,3-triazol-4-yl)-4-propylphenol;-   4-ethyl-5-methoxy-2-(5-p-tolyl-1H-1,2,3-triazol-4-yl)phenol;-   2-(5-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)-4-ethyl-5-methoxyphenol;-   4-ethyl-5-methoxy-2-(5-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)phenol;-   4-ethyl-5-methoxy-2-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenol;    or-   4-(4-bromophenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole;    -   or pharmaceutically acceptable salts, solvates, clathrates, or        prodrugs thereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   2-amino-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)acetamide    hydrochloride;-   2-amino-3-hydroxy-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)propanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)propanamide;-   2-amino-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4-(methylthio)butanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)butanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-phenylpropanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4-methylpentanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4-methylpentanamide    hydrochloride;-   1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3-methyl-1-oxobutan-2-aminium    chloride;-   1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3-methyl-1-oxopentan-2-aminium    chloride;-   3-hydroxy-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxobutan-2-aminium    chloride;-   3-(4-hydroxyphenyl)-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   2-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1,2,3-triazol-5-yl)phenylamino)-2-oxo-1-phenylethanaminium    chloride;-   3-(1H-indol-2-yl)-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   3-(benzofuran-2-yl)-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   3-carboxy-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   4-carboxy-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxobutan-2-aminium    chloride;-   5-amino-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1,5-dioxopentan-2-aminium    chloride;-   4-amino-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1,4-dioxobutan-2-aminium    chloride;-   3-(1H-imidazol-5-yl)-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopropan-2-aminium    chloride;-   6-amino-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxohexan-2-aminium    chloride;-   5-guanidino-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopentan-2-aminium    chloride;-   4-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-4-oxobutanoic    acid;-   5-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-5-oxopentanoic    acid;-   3-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3-oxopropan-1-aminium    chloride;-   N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(2-methoxyethoxy)propanamide;-   3-(2-PEG)-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)butyramide;-   N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(2-(methylamino)ethylamino)propanamide;-   3-PEG-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2-oxoethyl)butyramide;-   4-(2-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2-oxoethylamino)-4-oxobutanoic    acid;-   2-methoxyethyl    2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate;-   PEG-2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate;-   3-amino-4-(2-(5-guanidino-1-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1-oxopentan-2-ylamino)-2-oxoethylamino)-4-oxobutanoic    acid; or-   2-amino-N-(2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)propanamide    hydrochloride;    -   or pharmaceutically acceptable salts, solvates, clathrates, or        prodrugs thereof.

All of the features, specific embodiments and particular substituentsdisclosed herein may be combined in any combination. Each feature,embodiment or substituent disclosed in this specification may bereplaced by an alternative feature, embodiment or substituent servingthe same, equivalent, or similar purpose. In the case of chemicalcompounds, specific values for variables (e.g., values shown in theexemplary compounds disclosed herein) in any chemical formula disclosedherein can be combined in any combination resulting in a stablestructure. Furthermore, specific values (whether preferred or not) forsubstituents in one type of chemical structure may be combined withvalues for other substituents (whether preferred or not) in the same ordifferent type of chemical structure. Thus, unless expressly statedotherwise, each feature, embodiment or substituent disclosed is only anexample of a generic series of equivalent or similar features,embodiments or substituents.

In another embodiment, the invention relates to pharmaceuticalcompositions that comprise a compound of any one of formulas (I) through(XIX), (IA) through (XIA), (XVIIA) through (XIXA), (IB) through (XIB),(XVIIB) through (XIXB), or Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, as an active ingredient,and a pharmaceutically acceptable carrier or vehicle. The compositionsare useful for treating or preventing proliferative disorders such ascancer or macular degeneration.

In another embodiment, the invention relates to methods for inhibitingtubulin polymerization in a cell comprising contacting the cell with aneffective amount of a compound represented by any one of formulas (I)through (XIX), (IA) through (XIA), (XVIIA) through (XIXA), (IB) through(XIB), (XVIIB) through (XIXB), or Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof.

In another embodiment, the invention relates to methods for promotingmicrotubule depolymerization in a cell comprising contacting the cellwith an effective amount of a compound represented by any one offormulas (I) through (XIX), (IA) through (XIA), (XVIIA) through (XIXA),(IB) through (XIB), (XVIIB) through (XIXB), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, the invention relates to methods for treating orpreventing a proliferative disorder in a subject in need thereofcomprising administering an effective amount of a compound representedby any one of formulas (I) through (XIX), (IA) through (XIA), (XVIIA)through (XIXA), (IB) through (XIB), (XVIIB) through (XIXB), or Table 1,or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, the invention relates to methods for treatingcancer in a subject in need thereof comprising administering aneffective amount of a compound represented by any one of formulas (I)through (XIX), (IA) through (XIA), (XVIIA) through (XIXA), (IB) through(XIB), (XVIIB) through (XIXB), or Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof. In one aspectof this embodiment, the method involves treating a subject withmultidrug resistant cancer. In another aspect of this embodiment, themethod involves treating a subject having a solid tumor. In anotheraspect of this embodiment, the method involves treating a subject havinga hematological malignancy.

In another embodiment, the invention relates to methods for treatingcancer in a subject in need thereof comprising administering aneffective amount of a compound represented by any one of formulas (I)through (XIX), (IA) through (XIA), (XVIIA) through (XIXA), (IB) through(XIB), (XVIIB) through (XIXB), or Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof, and anadditional therapeutic agent. In one aspect of this embodiment, theadditional therapeutic agent is another anti-cancer agent.

In another embodiment, the invention relates to methods for blocking,occluding, or otherwise disrupting blood flow in neovasculature,comprising contacting the neovasculature with an effective amount of acompound represented by any one of formulas (I) through (XIX), (IA)through (XIA), (XVIIA) through (XIXA), (IB) through (XIB), (XVIIB)through (XIXB), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof, and an additional therapeuticagent.

In another embodiment, the invention relates to methods blocking,occluding, or otherwise disrupting blood flow in neovasculature in asubject, comprising administering to the subject an effective amount ofa compound represented by any one of formulas (I) through (XIX), (IA)through (XIA), (XVIIA) through (XIXA), (IB) through (XIB), (XVIIB)through (XIXB), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof, and an additional therapeuticagent.

Exemplary Compounds of the Invention

Exemplary compounds of the invention are depicted in Table 1 below.

TABLE 1 Compound No. Structure Chemical Name  1

1-(3,4,5-trimethoxy-phenyl)- 5-(4-bromo-phenyl)-1H- [1,2,3]triazole  2

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(naphthylen-2-yl)-1H-[1,2,3]triazole  3

1-(3,4,5-trimethoxy-phenyl)- 5-(4-methoxy-phenyl)-1H- [1,2,3]triazole  4

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(4-iodo-phenyl)-1H-[1,2,3]triazole  5

1-(3,4,5-trimethoxy-phenyl)- 5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole  6

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(4-bromo-phenyl)-1H-[1,2,3]triazole  7

1-(2-hydroxy-4-methoxy-5- (2,3-dihydro- benzo[1,4]dioxin-6-yl)-5-(4-bromo-phenyl)-1H- [1,2,3]triazole  8

1-(3,4,5-hydroxy-phenyl)-5- (4-hyoxy-phenyl)-1H- [1,2,3]triazole  9

1-(3,4,5-trimethoxy-phenyl)- 5-(4-iodo-phenyl)-1H- [1,2,3]triazole  10

1-(3,4,5-trimethoxy-phenyl)- 5-(3-fluoro-4-methoxy-phenyl)-1H-[1,2,3]triazole  11

1-(3,4,5-trimethoxy-phenyl)- 5-(4-nitro-phenyl)-1H- [1,2,3]triazole  12

1-(3,4,5-trimethoxy-phenyl)- 5-(4-amino-phenyl)-1H- [1,2,3]triazole  13

1-(3,4,5-trimethoxy-phenyl)- 5-(4′-methoxy-biphenyl-4-yl)-1H-[1,2,3]triazole  14

1-(3,4,5-trimethoxy-phenyl)- 5-[4-(pyridin-3-yl)-phenyl]-1H-[1,2,3]triazole  15

1-(3,4,5-trimethoxy-phenyl)- 5-[4-(pyridin-4-yl)-phenyl]-1H-[1,2,3]triazole  16

1-(3,4,5-trimethoxy-phenyl)- 5-[4-(pyridin-2-yl)-phenyl]-1H-[1,2,3]triazole  17

1-(3,4,5-trimethoxy-phenyl)- 5-(quinolin-7-yl)-1H- [1,2,3]triazole  18

1-(3,4,5-trimethoxy-phenyl)- 5-(pyridine-4-yl)-1H- [1,2,3]triazole  19

1-(3,4,5-trimethoxy-phenyl)- 5-(isoquinolin-7-yl)-1H- [1,2,3]triazole 20

1-(3,4,5-trimethoxy-phenyl)- 5-(1-methyl-1H-indol-5-yl)-1H-[1,2,3]triazole  21

1-(benzo[1,3]dioxol-5-yl)-5- (4-methoxy-phenyl)-1H- [1,2,3]triazole  22

1-(1-ethyl-1H-indol-6-yl)-5- (4-methoxy-phenyl)-1H- [1,2,3]triazole  23

1-(3,4,5-trimethoxy-phenyl)- 5-(4-carboxy-phenyl)-1H- [1,2,3]triazole 24

1-(3,4,5-trimethoxy-phenyl)- 5-(4-carbomethoxy-phenyl)-1H-[1,2,3]triazole  25

1-(3,4,5-trimethoxy-phenyl)- 5-[4-(oxazol-2-yl)-phenyl]-1H-[1,2,3]triazole  26

1-(3,4,5-triethyl-phenyl)-5-(4- methoxy-phenyl)-1H- [1,2,3]triazole  27

1-(3,4,5-triethyl-phenyl)-5-(4- iodo-phenyl)-1H- [1,2,3]triazole  28

1-(3,4,5-triethyl-phenyl)-5-(3- fluoro-4-methoxy-phenyl)-1H-[1,2,3]triazole  29

1-(3,4,5-triethyl-phenyl)-5-(4- nitro-phenyl)-1H- [1,2,3]triazole  30

1-(3,4,5-triethyl-phenyl)-5-[4- (N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole  31

1-(3,4,5-trimethyl-phenyl)-5- (4-methoxy-phenyl)-1H- [1,2,3]triazole  32

1-(3,4,5-triethyl-phenyl)-5-[4- (pyridin-3-yl)-phenyl]-1H-[1,2,3]triazole  33

1-(3,4,5-triethyl-phenyl)-5-[4- (pyridine-4-yl)-phenyl]-1H-[1,2,3]triazole  34

1-(3,4,5-triethyl-phenyl)-5-[4- (pyridine-2-yl)-phenyl]-1H-[1,2,3]triazole  35

1-(3,4,5-triethyl-phenyl)-5- (quinolin-7-yl)-1H- [1,2,3]triazole  36

1-(3,4,5-triethyl-phenyl)-5- (pyridine-4-yl)-1H- [1,2,3]triazole  37

1-(3,4,5-triethyl-phenyl)-5- (isoquinolin-7-yl)-1H- [1,2,3]triazole  38

1-(3,4,5-triethyl-phenyl)-5- (1H-indol-5-yl)-1H- [1,2,3]triazole  39

1-(benzo[1,3]dioxol-5-yl)-5- (4-methoxy-phenyl)-1H- [1,2,3]triazole  40

1-(1-isopropyl-1H-indol-6-yl)- 5-(4-methoxy-phenyl)-1H- [1,2,3]triazole 41

1-(2,3,4-trimethoxy-phenyl)- 5-(4-methoxy-phenyl)-1H- [1,2,3]triazole 42

1-(3,4,5-trimethoxy-phenyl)- 5-(3-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole  43

O-ethyl-O-{2-methoxy-5-[1- (3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazol-5-yl]- phenyl}-phosphate  44

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole  45

1-(3,4,5-trimethoxy-phenyl)- 5-(4-isopropyl-phenyl)-1H- [1,2,3]triazole 46

1-(3,4,5-trimethoxy-phenyl)- 5-(2,3-dihydro- benzo[1,4]dioxine-6-yl)-1H-[1,2,3]triazole  47

1-(3,4,5-trimethoxy-phenyl)- 5-(4-ethyl-phenyl)-1H- [1,2,3]triazole  48

1-(3,4,5-trimethoxy-phenyl)- 5-(5-methoxy-pyridine-2-yl)-1H-[1,2,3]triazole  49

1-(4,5,6-trimethoxy-pyridin-2- yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole  50

1-(3,5-dimethoxy-4- carbomethoxy-phenyl)-5-(4- methoxy-phenyl)-1H-[1,2,3]triazole  51

1-(3,5-diacetoxy-phenyl)-5- (4-methoxy-phenyl)-1H- [1,2,3]triazole  52

1-(3,4,5-trimethoxy-phenyl)- 5-(2-methoxy-pyridine-5-yl)-1H-[1,2,3]triazole  53

1-(1-methyl-5-methoxy-1H- indol-7-yl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole  54

1-(1-methyl-1H-indol-7-yl)-5- (4-methoxy-phenyl)-1H- [1,2,3]triazole  55

1-(Benzo[1,3]dioxol-4-yl)-5- (4-methoxy-phenyl)-1H- [1,2,3]triazole  56

1-(3,4,5-trimethoxy-phenyl)- 5-(2-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole  57

O-ethyl-O-{5-methoxy-2-[1- (3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazol-5-yl]- phenyl}-phosphate  58

1-(3,4,5-trimethoxy-phenyl)- 5-(pyridazin-4-yl)-1H- [1,2,3]triazole  59

1-(3,4,5-trimethoxy-phenyl)- 5-(pyrimidin-5-yl)-1H- [1,2,3]triazole  60

1-(3,4,5-trimethoxy-phenyl)- 5-(pyridin-2-yl)-1H- [1,2,3]triazole,hydrochloric acid salt  61

1-(3,4,5-trimethoxy-phenyl)- 5-(2-mercapto-4-methoxy-phenyl)-1H-[1,2,3]triazole  62

S-{2-methoxy-5-[1-(3,4,5- trimethoxy-phenyl)-1H-[1,2,3]triazol-5-yl]-phenyl}- thiophosphate, disodium salt  63

1-(3,4,5-trimethoxy-phenyl)- 5-(3-acetamido-4-methoxy-phenyl)-1H-[1,2,3]triazole  64

1-(3,4,5-trimethoxy-phenyl)- 5-(3-amino-4-methoxy-phenyl)-1H-[1,2,3]triazole, hydrochloric acid salt  65

1-(3,4,5-trimethoxy-phenyl)- 5-(2-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole  66

1-(3,4,5-trimethoxy-phenyl)- 5-(2-methoxy-pyridin-5-yl)-1H-[1,2,3]triazole  67

1-(3,4,5-trimethoxy-phenyl)- 5-(5-methoxy-pyridin-2-yl)-1H-[1,2,3]triazole  68

1-(3,4,5-trimethoxy-phenyl)- 5-(3-carboxy-4-methoxy-phenyl)-1H-[1,2,3]triazole, sodium salt  69

1-(3,4,5-trimethoxy-phenyl)- 5-(3-methoxycarbonyl-4- methoxy-phenyl)-1H-[1,2,3]triazole  70

1-(3,4,5-trimethoxy-phenyl)- 5-(3-sulfooxy-4-methoxy-phenyl)-1H-[1,2,3]triazole, sodium salt  71

1-(3,4,5-trimethoxy-phenyl)- 5-(2-amino-4-methoxy-phenyl)-1H-[1,2,3]triazole  72

1-(3,4,5-trimethoxy-phenyl)- 5-(3-phosphonooxy-4,5-dimethoxy-phenyl)-1H- [1,2,3]triazole, disodium salt  73

1-(3,4,5-trimethoxy-phenyl)- 5-(2-phosphonooxy-4- methoxy-phenyl)-1H-[1,2,3]triazole, disodium salt  74

1-(3,4,5-trimethoxy-phenyl)- 5-(4-methylsulfanyl-phenyl)-1H-[1,2,3]triazole  75

1-(3,4,5-trimethoxy-phenyl)- 5-(3-phosphonooxy-4-methylsulfanyl-phenyl)-1H- [1,2,3]triazole, disodium salt  76

1-(3,4,5-trimethoxy-phenyl)- 5-(3-amino-4-methylsulfanyl-phenyl)-1H-[1,2,3]triazole  77

1-(3,4,5-trimethoxy-phenyl)- 5-(2,3-dihydro-benzofuran-6-yl)-1H-[1,2,3]triazole  78

1-(3,4,5-trimethoxy-phenyl)- 5-(4-hydroxy-phenyl)-1H- [1,2,3]triazole,sodium salt  79

1-(3,4,5-trimethoxy-phenyl)- 5-(4-phosphonooxy-phenyl)-1H-[1,2,3]triazole, disodium salt  80

1-(3,4,5-trimethoxy-phenyl)- 5-[4-(tetrazol-5-yl)-phenyl]-1H-[1,2,3]triazole  81

1-(3,4,5-trimethoxy-phenyl)- 5-[4-(1-methyl-tetrazol-5-yl)-phenyl]-1H-[1,2,3]triazole  82

1-(3,4,5-trimethoxy-phenyl)- 5-(1-methyl-1H-indol-5-yl)-1H-[1,2,3]triazole  83

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5- (pyridazin-4-yl)-1H-[1,2,3]triazole  84

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5- (pyrimidin-5-yl)-1H-[1,2,3]triazole  85

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5- (pyridin-3-yl)-1H-[1,2,3]triazole, hydrochloric acid salt  86

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- mercapto-4-methoxy-phenyl)-1H-[1,2,3]triazole  87

S-{2-methoxy-5-[1-(7- methoxy-benzo[1,3]dioxol-5-yl)-1H-[1,2,3]triazol-5-yl]- phenyl}-thiophosphate, disodium salt  88

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- acetamido-4-methoxy-phenyl)-1H-[1,2,3]triazole  89

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- amino-4-methoxy-phenyl)-1H-[1,2,3]triazole, hydrochloric acid salt  90

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(2- hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole  91

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(2- methoxy-pyridin-5-yl)-1H-[1,2,3]triazole  92

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(5- methoxy-pyridin-2-yl)-1H-[1,2,3]triazole  93

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- carboxy-4-methoxy-phenyl)-1H-[1,2,3]triazole  94

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- methoxycarbonyl-4-methoxy-phenyl)-1H-[1,2,3]triazole  95

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- sulfooxy-4-methoxy-phenyl)-1H-[1,2,3]triazole, sodium salt  96

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(2- amino-4-methoxy-phenyl)-1H-[1,2,3]triazole  97

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- phosphonyl-4,5-dimethoxy-phenyl)-1H-[1,2,3]triazole, disodium salt  98

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(2- phosphonyl-4-methoxy-phenyl)-1H-[1,2,3]triazole, sodium salt  99

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(4- methylsulfanyl-phenyl)-1H-[1,2,3]triazole 100

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- phosphonyl-4-methylsulfanyl-phenyl)-1H- [1,2,3]triazole, disodium salt 101

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(3- amino-4-methylsulfanyl-phenyl)-1H-[1,2,3]triazole 102

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(2,3-dihydro-benzofuran-6-yl)-1H- [1,2,3]triazole 103

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(4- hydroxy-phenyl)-1H-[1,2,3]triazole, sodium salt 104

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(4- phosphonooxy-phenyl)-1H-[1,2,3]triazole, disodium salt 105

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-[1H- tetrazol-5-yl)-phenyl]-1H-[1,2,3]triazole 106

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-[1- methyl-1H-tetrazol-5-yl)-phenyl]-1H-[1,2,3]triazole 107

1-(7-methoxy- benzo[1,3]dioxol-5-yl)-5-(1- methyl-1H-indol-5-yl)-1H-[1,2,3]triazole 108

1-(1-methyl-1H-indol-5-yl)-5- (3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole 109

1-(3-phosphonooxy-4- methoxy-phenyl)-5-(3,4,5- trimethoxy-phenyl)-1H-[1,2,3]triazole, disodium salt 110

1-[4-(N,N-dimethylamino)- phenyl]-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole 111

1-(3-amino-4-methoxy- phenyl)-5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole, hydrochloric acid salt 112

2-hydroxy-1-{2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)-[1,2,3]triazol-1-yl]- phenylcarbamoyl}-ethyl- ammonium chloride 113

1-(2,4,5-trimethoxy-phenyl)- 5-(4-methoxy-phenyl)-1H- [1,2,3]triazole114

1-(2,4,5-trimethoxy-phenyl)- 5-(4-methyl-phenyl)-1H- [1,2,3]triazole 115

1-(2,4,5-trimethoxy-phenyl)- 5-(4-ethoxy-phenyl)-1H- [1,2,3]triazole 116

1-(2,4,5-trimethoxy-phenyl)- 5-(4-ethyl-phenyl)-1H- [1,2,3]triazole 117

1-(2,4,5-trimethoxy-phenyl)- 5-(4-propoxy-phenyl)-1H- [1,2,3]triazole118

1-(2,4,5-trimethoxy-phenyl)- 5-(4-propyl-phenyl)-1H- [1,2,3]triazole 119

1-(2,4,5-trimethoxy-phenyl)- 5-(4-butoxy-phenyl)-1H- [1,2,3]triazole 120

1-(2,4,5-trimethoxy-phenyl)- 5-(4-butyl-phenyl)-1H- [1,2,3]triazole 121

1-(2,4,5-trimethoxy-phenyl)- 5-(4-bromo-phenyl)-1H- [1,2,3]triazole 122

1-(2,4,5-trimethoxy-phenyl)- 5-(4-chloro-phenyl)-1H- [1,2,3]triazole 123

1-(2,4,5-trimethoxy-phenyl)- 5-(4-fluoro-phenyl)-1H- [1,2,3]triazole 124

1-(2,4,5-trimethoxy-phenyl)- 5-(4-nitro-phenyl)-1H- [1,2,3]triazole 125

1-(2,4,5-trimethoxy-phenyl)- 5-[4-(N,N-diethylamino)-phenyl]-1H-[1,2,3]triazole 126

1-(2,4,5-trimethoxy-phenyl)- 5-(3,4-dimethoxy-phenyl)-1H-[1,2,3]triazole 127

1-(2,4,5-trimethoxy-phenyl)- 5-(3-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole 128

1-(2,4,5-trimethoxy-phenyl)- 5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole 129

1-(2,3,5-trimethoxy-phenyl)- 5-(4-methoxy-phenyl)-1H- [1,2,3]triazole130

1-(2,3,5-trimethoxy-phenyl)- 5-(4-methyl-phenyl)-1H- [1,2,3]triazole 131

1-(2,3,5-trimethoxy-phenyl)- 5-(4-ethoxy-phenyl)-1H- [1,2,3]triazole 132

1-(2,3,5-trimethoxy-phenyl)- 5-(4-ethyl-phenyl)-1H- [1,2,3]triazole 133

1-(2,3,5-trimethoxy-phenyl)- 5-(4-propoxy-phenyl)-1H- [1,2,3]triazole134

1-(2,3,5-trimethoxy-phenyl)- 5-(4-propyl-phenyl)-1H- [1,2,3]triazole 135

1-(2,3,5-trimethoxy-phenyl)- 5-(4-butoxy-phenyl)-1H- [1,2,3]triazole 136

1-(2,3,5-trimethoxy-phenyl)- 5-(4-butyl-phenyl)-1H- [1,2,3]triazole 137

1-(2,3,5-trimethoxy-phenyl)- 5-(4-bromo-phenyl)-1H- [1,2,3]triazole 138

1-(2,3,5-trimethoxy-phenyl)- 5-(4-chloro-phenyl)-1H- [1,2,3]triazole 139

1-(2,3,5-trimethoxy-phenyl)- 5-(4-fluoro-phenyl)-1H- [1,2,3]triazole 140

1-(2,3,5-trimethoxy-phenyl)- 5-(4-nitro-phenyl)-1H- [1,2,3]triazole 141

1-(2,3,5-trimethoxy-phenyl)- 5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole 142

1-(2,3,5-trimethoxy-phenyl)- 5-(3,4-dimethoxy-phenyl)-1H-[1,2,3]triazole 143

1-(2,3,5-trimethoxy-phenyl)- 5-(3-hydroxy-4-methoxy-phenyl)-1H-[1,2,3]triazole 144

1-(2,3,5-trimethoxy-phenyl)- 5-(3,4,5-trimethoxy-phenyl)-1H-[1,2,3]triazole 145

1-(4-methoxy-phenyl)-5- (2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole 146

1-(4-methyl-phenyl)-5- (2,3,4,5-tetramethoxy- phenyl)-1H-[1,2,3]triazole147

1-(4-ethoxy-phenyl)-5- (2,3,4,5-tetramethoxy- phenyl)-1H-[1,2,3]triazole148

1-(4-ethyl-phenyl)-5-(2,3,4,5- tetramethoxy-phenyl)-1H- [1,2,3]triazole149

1-(4-propoxy-phenyl)-5- (2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole 150

1-(4-propyl-phenyl)-5- (2,3,4,5-tetramethoxy- phenyl)-1H-[1,2,3]triazole151

1-(4-butoxy-phenyl)-5- (2,3,4,5-tetramethoxy- phenyl)-1H-[1,2,3]triazole152

1-(4-butyl-phenyl)-5-(2,3,4,5- tetramethoxy-phenyl)-1H- [1,2,3]triazole153

1-(4-bromo-phenyl)-5- (2,3,4,5-tetramethoxy- phenyl)-1H-[1,2,3]triazole154

1-(4-chloro-phenyl)-5- (2,3,4,5-tetramethoxy- phenyl)-1H-[1,2,3]triazole155

1-(4-fluoro-phenyl)-5- (2,3,4,5-tetramethoxy- phenyl)-1H-[1,2,3]triazole156

1-(4-nitro-phenyl)-5-(2,3,4,5- tetramethoxy-phenyl)-1H- [1,2,3]triazole157

1-[4-(N,N-dimethylamino)- phenyl]-5-(2,3,4,5- tetramethoxy-phenyl)-1H-[1,2,3]triazole 158

1-(3,4-dimethoxy-phenyl)-5- (2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole 159

1-(3-hydroxy-4-methoxy- phenyl)-5-(2,3,4,5- tetramethoxy-phenyl)-1H-[1,2,3]triazole 160

1-(3,4,5-trimethoxy-phenyl)- 5-(2,3,4,5-tetramethoxy-phenyl)-1H-[1,2,3]triazole 161

1-(3,4-trimethoxy-phenyl)-5- (2,3-dihydro- benzo[1,4]dioxin-6-yl)-1H-[1,2,3]triazole 162

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(3,4- dimethyl-phenyl)-1H-[1,2,3]triazole 163

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(4-chloro-phenyl)-1H-[1,2,3]triazole 164

1-(2-hydroxy-4-methoxy-5- propyl-phenyl)-5-phenyl-1H- [1,2,3]triazole165

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(4-methyl-phenyl)-1H-[1,2,3]triazole 166

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(4-amino-phenyl)-1H-[1,2,3]triazole 167

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(4-trifluoromethyl-phenyl)-1H- [1,2,3]triazole 168

1-(2-hydroxy-4-methoxy-5- ethyl-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole 169

1-(4-bromo-phenyl)-5-(3,4,5- trimethoxy-phenyl)-1H- [1,2,3]triazole 170

2-amino-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenyl)acetamide hydrochloride 171

2-amino-3-hydroxy-N-(2- methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenyl)propanamide hydrochloride 172

2-amino-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenyl)propanamide 173

2-amino-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4- (methylthio)butanamide hydrochloride 174

2-amino-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenyl)butanamide hydrochloride 175

2-amino-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3- phenylpropanamide hydrochloride 176

2-amino-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4- methylpentanamide hydrochloride 177

2-amino-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3- (4-methoxyphenyl) propanamidehydrochloride 178

2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenyldihydrogen phosphate 179

sodium 2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl phosphate 180

1-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3- methyl-1-oxobutan-2- aminium chloride 181

1-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3- methyl-1-oxopentan-2- aminium chloride 182

3-hydroxy-1-(2-methoxy-5- (1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylamino)-1-oxobutan- 2-aminium chloride 183

3-(4-hydroxyphenyl)-1-(2- methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenylamino)-1-oxopropan-2-aminium chloride 184

2-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2- oxo-1-phenylethanaminium chloride 185

3-(1H-indol-2-yl)-1-(2- methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1- oxopropan-2-aminium chloride 186

3-(benzofuran-2-yl)-1-(2- methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenylamino)-1-oxopropan-2-aminium chloride 187

3-carboxy-1-(2-methoxy-5- (1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylamino)-1- oxopropan-2-aminium chloride 188

4-carboxy-1-(2-methoxy-5- (1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylamino)-1-oxobutan- 2-aminium chloride 189

5-amino-1-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenylamino)-1,5- dioxopentan-2-aminium chloride 190

4-amino-1-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenylamino)-1,4- dioxobutan-2-aminium chloride 191

3-(1H-imidazol-5-yl)-1-(2- methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenylamino)-1-oxopropan-2-aminium chloride 192

6-amino-1-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenylamino)-1-oxohexan- 2-aminium chloride 193

5-guanidino-1-(2-methoxy-5- (1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylamino)-1- oxopentan-2-aminium chloride 194

4-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-4- oxobutanoic acid 195

5-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-5- oxopentanoic acid 196

3-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3- oxopropan-1-aminium chloride 197

N-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(2- methoxyethoxy)propanamide 198

3-(2-PEG)-N-(2-methoxy-5- (1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenyl)butyramide 199

N-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(2- (methylamino)ethylamino) propanamide 200

3-PEG-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenylamino)-2- oxoethyl)butyramide 201

4-(2-(2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2- oxoethylamino)-4- oxobutanoic acid 202

2-methoxyethyl 2-methoxy-5- (1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylcarbamate 203

PEG-2-methoxy-5-(1-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate 204

3-amino-4-(5-guanidino-1-(2- methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenylamino)-1-oxopentan-2-ylamino)-2- oxoethylamino)-4- oxobutanoic acid 205

2-amino-N-(2-methoxy-5-(1- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenyl)propanamide hydrochloride  1b

4-(3,4,5-trimethoxy-phenyl)- 5-(4-bromo-phenyl)-1H- [1,2,3]triazole  2b

4-ethyl-5-methoxy-2-(5- (naphthalen-2-yl)-1H-1,2,3- triazol-4-yl)phenol 3b

5-(4-methoxyphenyl)-4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazole  4b

4-ethyl-2-(5-(4-iodophenyl)- 1H-1,2,3-triazol-4-yl)-5- methoxyphenol  5b

N,N-dimethyl-4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline  6b

2-(5-(4-bromophenyl)-1H- 1,2,3-triazol-4-yl)-4-ethyl-5- methoxyphenol 7b

2-(5-(2,3- dihydrobenzo[b][1,4]dioxin-6- yl)-1H-1,2,3-triazol-4-yl)-5-methoxy-4-propylphenol  8b

5-(5-(4-hydroxyphenyl)-1H- 1,2,3-triazol-4-yl)benzene- 1,2,3-triol  9b

5-(4-iodophenyl)-4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazole  10b

5-(3-fluoro-4- methoxyphenyl)-4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazole  11b

5-(4-nitrophenyl)-4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazole  12b

4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)aniline  13b

5-(4′-methoxybiphenyl-4-yl)- 4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole  14b

3-(4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenyl)pyridine 15b

4-(4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenyl)pyridine 16b

2-(4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenyl)pyridine 17b

7-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)quinoline  18b

4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)pyridine  19b

7-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)isoquinoline  20b

1-methyl-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)-1H-indole  21b

4-(benzo[d][1,3]dioxol-5-yl)- 5-(4-methoxyphenyl)-1H- 1,2,3-triazole 22b

1-ethyl-6-(5-(4- methoxyphenyl)-1H-1,2,3- triazole-4-yl)-1H-indole  23b

4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)benzoic acid  24b

methyl 4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)benzoate 25b

2-(4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenyl)oxazole 26b

5-(4-methoxyphenyl)-4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazole  27b

5-(4-iodophenyl)-4-(3,4,5- triethylphenyl)-1H-1,2,3- triazole  28b

5-(3-fluoro-4- methoxyphenyl)-4-(3,4,5- triethylphenyl)-1H-1,2,3-triazole  29b

5-(4-nitrophenyl)-4-(3,4,5- triethylphenyl)-1H-1,2,3- triazole  30b

N,N-dimethyl-4-(4-(3,4,5- triethylphenyl)-1H-1,2,3- triazol-5-yl)aniline 31b

5-(4-methoxyphenyl)-4- (3,4,5-trimethylphenyl)-1H- 1,2,3-triazole  32b

3-(4-(4-(3,4,5-triethylphenyl)- 1H-1,2,3-triazol-5- yl)phenyl)pyridine 33b

4-(4-(4-(3,4,5-triethylphenyl)- 1H-1,2,3-triazol-5- yl)phenyl)pyridine 34b

2-(4-(4-(3,4,5-triethylphenyl)- 1H-1,2,3-triazol-5- yl)phenyl)pyridine 35b

7-(4-(3,4,5-triethylphenyl)- 1H-1,2,3-triazol-5- yl)quinoline  36b

4-(4-(3,4,5-triethylphenyl)- 1H-1,2,3-triazol-5-yl)pyridine  37b

7-(4-(3,4,5-triethylphenyl)- 1H-1,2,3-triazol-5- yl)isoquinoline  38b

5-(4-(3,4,5-triethylphenyl)- 1H-1,2,3-triazol-5-yl)-1H- indole  39b

4-(benzo[d][1,3]dioxol-5-yl)- 5-(4-methoxyphenyl)-1H- 1,2,3-triazole 40b

1-isopropyl-6-(5-(4- methoxyphenyl)-1H-1,2,3- triazol-4-yl)-1H-indole 41b

5-(4-methoxyphenyl)-4- (2,3,4-trimethoxyphenyl)-1H- 1,2,3-triazole  42b

2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenol 43b

ethyl 2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl hydrogen phosphate  44b

4-ethyl-2-(5-(4- methoxyphenyl)-1H-1,2,3- triazol-4-yl)-5-methoxyphenol 45b

5-(4-isopropylphenyl)-4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazole 46b

5-(2,3- dihydrobenzo[b][1,4]dioxin-6- yl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazole  47b

5-(4-ethylphenyl)-4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazole  48b

5-methoxy-2-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)pyridine 49b

6-(5-(4-methoxyphenyl)-1H- 1,2,3-triazol-4-yl)-2,3,4- trimethoxypyridine 50b

methyl 2,6-dimethoxy-4-(5- (4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)benzoate  51b

5-(5-(4-methoxyphenyl)-1H- 1,2,3-triazol-4-yl)-1,3- phenylene diacetate 52b

2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)pyridine 53b

5-methoxy-7-(5-(4- methoxyphenyl)-1H-1,2,3- triazol-4-yl)-1-methyl-1H-indole  54b

1-ethyl-7-(5-(4- methoxyphenyl)-1H-1,2,3- triazol-4-yl)-1H-indole  55b

4-(benzo[d][1,3]dioxol-4-yl)- 5-(4-methoxyphenyl)-1H- 1,2,3-triazole 56b

5-methoxy-2-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenol 57b

ethyl 5-methoxy-2-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl hydrogen phosphate  58b

4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)pyridazine  59b

5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)pyrimidine  60b

3-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)pyridinehydrochloride  61b

2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzenethiol  62b

sodium S-2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl phosphorothioate  63b

N-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)acetamide  64b

2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzenaminium chloride  65b

5-methoxy-2-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenol 66b

2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)pyridine 67b

5-methoxy-2-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)pyridine 68b

sodium 2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzoate  69b

methyl 2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzoate  70b

sodium 2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl sulfate  71b

5-methoxy-2-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)aniline 72b

sodium 2,3-dimethoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl phosphate  73b

sodium 5-methoxy-2-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl phosphate  74b

5-(4-(methylthio)phenyl)-4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazole 75b

sodium 2-(methylthio)-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl phosphate  76b

2-(methylthio)-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline  77b

5-(2,3-dihydrobenzofuran-6- yl)-4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazole  78b

sodium 4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenolate 79b

monosodium monosodium(II) mono(4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl phosphate)  80b

5-(4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenyl)-1H-tetrazole  81b

1-methyl-5-(4-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-1H- tetrazole  82b

1-methyl-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)-1H-indole  83b

4-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)pyridazine  84b

5-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)pyrimidine  85b

3-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)pyridine hydrochloride  86b

2-methoxy-5-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)benzenethiol  87b

sodium S-2-methoxy-5-(4-(7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5- yl)phenyl phosphorothioate  88b

N-(2-methoxy-5-(4-(7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5- yl)phenyl)acetamide  89b

2-methoxy-5-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)benzenaminium chloride  90b

5-methoxy-2-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)phenol  91b

2-methoxy-5-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)pyridine  92b

5-methoxy-2-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)pyridine  93b

sodium 2-methoxy-5-(4-(7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5- yl)benzoate  94b

methyl 2-methoxy-5-(4-(7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5- yl)benzoate  95b

sodium 2-methoxy-5-(4-(7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5- yl)phenyl sulfate  96b

5-methoxy-2-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)aniline  97b

sodium 2,3-dimethoxy-5-(4- (7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5- yl)phenyl phosphate  98b

sodium 5-methoxy-2-(4-(7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5- yl)phenyl phosphate  99b

4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-5-(4- (methylthio)phenyl)-1H-1,2,3-triazole 100b

sodium 5-(4-(7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-5-yl)-2- (methylthio)phenyl phosphate 101b

5-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)-2-(methylthio)aniline 102b

5-(2,3-dihydrobenzofuran-6- yl)-4-(7- methoxybenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole 103b

sodium 4-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)phenolate 104b

sodium 4-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)phenyl phosphate 105b

5-(4-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)phenyl)-1H-tetrazole 106b

5-(4-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)phenyl)-1-methyl-1H- tetrazole 107b

5-(4-(7- methoxybenzo[d][1,3]dioxol- 5-yl)-1H-1,2,3-triazol-5-yl)-1-methyl-1H-indole 108b

1-methyl-5-(5-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indole 109b

monosodium monosodium(II) mono(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-4-yl)phenyl phosphate) 110b

N,N-dimethyl-4-(5-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)aniline 111b

2-methoxy-5-(5-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)benzenaminium chloride 112b

3-hydroxy-1-(2-methoxy-5- (5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4- yl)phenylamino)-1- oxopropan-2-aminium chloride 113b

5-(4-methoxyphenyl)-4- (2,4,5-trimethoxyphenyl)-1H- 1,2,3-triazole 114b

5-p-tolyl-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 115b

5-(4-ethoxyphenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 116b

5-(4-ethylphenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 117b

5-(4-propoxyphenyl)-4- (2,4,5-trimethoxyphenyl)-1H- 1,2,3-triazole 118b

5-(4-propylphenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 119b

5-(4-butoxyphenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 120b

5-(4-butylphenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 121b

5-(4-bromophenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 122b

5-(4-chlorophenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 123b

5-(4-fluorophenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 124b

5-(4-nitrophenyl)-4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 125b

N,N-dimethyl-4-(4-(2,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline 126b

5-(3,4-dimethoxyphenyl)-4- (2,4,5-trimethoxyphenyl)-1H- 1,2,3-triazole127b

2-methoxy-5-(4-(2,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenol128b

4-(2,4,5-trimethoxyphenyl)-5- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole 129b

5-(4-methoxyphenyl)-4- (2,3,5-trimethoxyphenyl)-1H- 1,2,3-triazole 130b

5-p-tolyl-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 131b

5-(4-ethoxyphenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 132b

5-(4-ethylphenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 133b

5-(4-propoxyphenyl)-4- (2,3,5-trimethoxyphenyl)-1H- 1,2,3-triazole 134b

5-(4-propylphenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 135b

5-(4-butoxyphenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 136b

5-(4-butylphenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 137b

5-(4-bromophenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 138b

5-(4-chlorophenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 139b

5-(4-fluorophenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 140b

5-(4-nitrophenyl)-4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazole 141b

N,N-dimethyl-4-(4-(2,3,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline 142b

5-(3,4-dimethoxyphenyl)-4- (2,3,5-trimethoxyphenyl)-1H- 1,2,3-triazole143b

2-methoxy-5-(4-(2,3,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenol144b

4-(2,3,5-trimethoxyphenyl)-5- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole 145b

4-(4-methoxyphenyl)-5- (2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole146b

5-(2,3,4,5- tetramethoxyphenyl)-4-p- tolyl-1H-1,2,3-triazole 147b

4-(4-ethoxyphenyl)-5- (2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole148b

4-(4-ethylphenyl)-5-(2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole149b

4-(4-propoxyphenyl)-5- (2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole150b

4-(4-propylphenyl)-5- (2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole151b

4-(4-butoxyphenyl)-5- (2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole152b

4-(4-butylphenyl)-5-(2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole153b

4-(4-bromophenyl)-5- (2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole154b

4-(4-chlorophenyl)-5- (2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole155b

4-(4-fluorophenyl)-5-(2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole156b

4-(4-nitrophenyl)-5-(2,3,4,5- tetramethoxyphenyl)-1H- 1,2,3-triazole157b

N,N-dimethyl-4-(5-(2,3,4,5- tetramethoxyphenyl)-1H-1,2,3-triazol-4-yl)aniline 158b

4-(3,4-dimethoxyphenyl)-5- (2,3,4,5- tetramethoxyphenyl)-1H-1,2,3-triazole 159b

2-methoxy-5-(5-(2,3,4,5- tetramethoxyphenyl)-1H-1,2,3-triazol-4-yl)phenol 160b

5-(2,3,4,5- tetramethoxyphenyl)-4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole 161b

5-(2,3- dihydrobenzo[b][1,4]dioxin-6- yl)-4-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole 162b

2-(5-(3,4-dimethylphenyl)- 1H-1,2,3-triazol-4-yl)-4-ethyl-5-methoxyphenol 163b

2-(5-(4-chlorophenyl)-1H- 1,2,3-triazol-4-yl)-4-ethyl-5- methoxyphenol164b

5-methoxy-2-(5-phenyl-1H- 1,2,3-triazol-4-yl)-4- propylphenol 165b

4-ethyl-5-methoxy-2-(5-p- tolyl-1H-1,2,3-triazol-4- yl)phenol 166b

2-(5-(4-aminophenyl)-1H- 1,2,3-triazol-4-yl)-4-ethyl-5- methoxyphenol167b

4-ethyl-5-methoxy-2-(5-(4- (trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)phenol 168b

4-ethyl-5-methoxy-2-(5-(4- methoxyphenyl)-1H-1,2,3- triazol-4-yl)phenol169b

4-(4-bromophenyl)-5-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazole 170b

2-amino-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenyl)acetamide hydrochloride 171b

2-amino-3-hydroxy-N-(2- methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenyl)propanamide hydrochloride 172b

2-amino-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenyl)propanamide 173b

2-amino-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4- (methylthio)butanamide hydrochloride 174b

2-amino-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenyl)butanamide hydrochloride 175b

2-amino-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3- phenylpropanamide hydrochloride 176b

2-amino-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4- methylpentanamide hydrochloride 177b

2-amino-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-4- methylpentanamide hydrochloride 178b

2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenyldihydrogen phosphate 179b

sodium 2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl phosphate 180b

1-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3- methyl-1-oxobutan-2- aminium chloride 181b

1-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3- methyl-1-oxopentan-2- aminium chloride 182b

3-hydroxy-1-(2-methoxy-5- (4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylamino)-1-oxobutan- 2-aminium chloride 183b

3-(4-hydroxyphenyl)-1-(2- methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenylamino)-1-oxopropan-2-aminium chloride 184b

2-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2- oxo-1-phenylethanaminium chloride 185b

3-(1H-indol-2-yl)-1-(2- methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-1- oxopropan-2-aminium chloride 186b

3-(benzofuran-2-yl)-1-(2- methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-2-yl)phenylamino)-1-oxopropan-2-aminium chloride 187b

3-carboxy-1-(2-methoxy-5- (4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylamino)-1- oxopropan-2-aminium chloride 188b

4-carboxy-1-(2-methoxy-5- (4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylamino)-1-oxobutan- 2-aminium chloride 189b

5-amino-1-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenylamino)-1,5- dioxopentan-2-aminium chloride 190b

4-amino-1-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenylamino)-1,4- dioxobutan-2-aminium chloride 191b

3-(1H-imidazol-5-yl)-1-(2- methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenylamino)-1-oxopropan-2-aminium chloride 192b

6-amino-1-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenylamino)-1-oxohexan- 2-aminium chloride 193b

5-guanidino-1-(2-methoxy-5- (4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylamino)-1- oxopentan-2-aminium chloride 194b

4-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-4- oxobutanoic acid 195b

5-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-5- oxopentanoic acid 196b

3-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-3- oxopropan-1-aminium chloride 197b

N-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(2- methoxyethoxy)propanamide 198b

3-(2-PEG)-N-(2-methoxy-5- (4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenyl)butyramide 199b

N-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-(2- (methylamino)ethylamino) propanamide 200b

3-PEG-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenylamino)-2- oxoethyl)butyramide 201b

4-(2-(2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2- oxoethylamino)-4- oxobutanoic acid 202b

2-methoxyethyl 2-methoxy-5- (4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5- yl)phenylcarbamate 203b

PEG-2-methoxy-5-(4-(3,4,5- trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate 204b

3-amino-4-(2-(5-guanidino-1- (2-methoxy-5-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)phenylamino)-1-oxopentan-2-ylamino)-2- oxoethylamino)-4- oxobutanoic acid 205b

2-amino-N-(2-methoxy-5-(4- (3,4,5-trimethoxyphenyl)-1H- 1,2,3-triazol-5-yl)phenyl)propanamide hydrochloride

Methods of Making the Compounds of the Invention

The compounds of the invention can be made by the methods describedherein in Example 1. Typically, an aromatic amine compound (a) istreated with a nitrite salt, such as sodium nitrite, in HCl and waterfollowed by treatment with an azide salt, such as sodium azide, to forman aromatic azide (b). The aromatic azide (b) is then heated with analkyne which is substituted with an aromatic group (c) to form the[1,2,3]triazole ring (I) (see scheme I).

Other methods of preparing 1,2,3-triazoles are described in Pati, Hari,N., et al., (2005). “Synthesis and biological evaluation ofcis-combretastatin analogs and their novel 1,2,3-triazole derivatives.”Heterocycl. Commun., 11(2), 117-120, which is incorporated by referenceherein in its entirety. In general, Wittig reagents are reacted withsubstituted benzaldehydes and then 1,2,3-triazoles are producedaccording to scheme II below.

Methods of Treatment and Prevention

In one embodiment, the invention provides a method of inhibiting tubulinpolymerization in a cell, comprising contacting the cell with aneffective amount of a compound of any one of formulas (I) through (XIX),(IA) through (XIA), (XVIIA) through (XIXA), (IB) through (XIB), (XVIIB)through (XIXB), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, and prodrug thereof, or a pharmaceutical compositioncomprising a compound of any one of formulas (I) through (XIX), (IA)through (XIA), (XVIIA) through (XIXA), (IB) through (XIB), (XVIIB)through (XIXB), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, and prodrug thereof. Inhibition of tubulinpolymerization can be determined by determining the IC₅₀ for tubulinpolymerization inhibition for a compound as described above, or by usingthe methods described in Examples 3, 4 and 5, herein.

In another embodiment, the invention provides a method of treating aproliferative disorder, such as cancer, in a subject in need thereof,comprising administering to the subject an effective amount of acompound of any one of formulas (I) through (XIX), (IA) through (XIA),(XVIIA) through (XIXA), (IB) through (XIB), (XVIIB) through (XIXB), orTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, andprodrug thereof, or a pharmaceutical composition comprising a compoundof any one of formulas (I) through (XIX), (IA) through (XIA), (XVIIA)through (XIXA), (IB) through (XIB), (XVIIB) through (XIXB), or Table 1,or a pharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof. Such patients may be treatment naïve or may experience partialor no response to conventional therapies.

Responsiveness to treatment with the compounds of the invention in thecase of proliferative disorders, can be measured by reduction in theextent or severity of the symptoms associated with the disease ordisorder and/or an increase in the longevity and/or quality of life ofthe subject compared with the absence of the treatment. Responsivenessto treatment with the compounds of the invention in the case of cancer,can be measured by a reduction in tumor mass, a reduction in the rate oftumor growth, a reduction in metastasis, a reduction in the severity ofthe symptoms associated with the cancer and/or an increase in thelongevity of the subject compared with the absence of the treatment.

Combination Therapies

The invention also provides methods of preventing, treating, managing,or ameliorating a proliferative disorder, such as cancer, or one or moresymptoms thereof, said methods comprising administering to a subject inneed thereof one or more compounds of the invention and one or moreother therapies (e.g., one or more prophylactic or therapeutic agentsthat are currently being used, have been used, are known to be useful orin development for use in the prevention, treatment or amelioration of aproliferative disorder, such as cancer, or one or more symptomsassociated with said proliferative disorder).

The prophylactic or therapeutic agents of the combination therapies ofthe invention can be administered sequentially or concurrently. In aspecific embodiment, the combination therapies of the invention compriseone or more compounds and at least one other therapy (e.g., anotherprophylactic or therapeutic agent) which has the same mechanism ofaction as said compounds (e.g., a therapeutic agent that inhibitstubulin polymerization). In another specific embodiment, the combinationtherapies of the invention comprise one or more compounds of theinvention and at least one other therapy (e.g., another prophylactic ortherapeutic agent) which has a different mechanism of action than saidcompounds. In certain embodiments, the combination therapies of thepresent invention improve the prophylactic or therapeutic effect of oneor more compounds of the invention by functioning together with thecompounds to have an additive or synergistic effect. In certainembodiments, the combination therapies of the present invention reducethe side effects associated with the therapies (e.g., prophylactic ortherapeutic agents). In certain embodiments, the combination therapiesof the present invention reduce the effective dosage of one or more ofthe therapies.

The prophylactic or therapeutic agents of the combination therapies canbe administered to a subject, preferably a human subject, in the samepharmaceutical composition. In alternative embodiments, the prophylacticor therapeutic agents of the combination therapies can be administeredconcurrently to a subject in separate pharmaceutical compositions. Theprophylactic or therapeutic agents may be administered to a subject bythe same or different routes of administration.

In a specific embodiment, a pharmaceutical composition comprising one ormore compounds of the invention is administered to a subject, preferablya human, to prevent, treat, manage, or ameliorate a proliferativedisorder, such as cancer, or one or more symptom thereof. In accordancewith the invention, pharmaceutical compositions of the invention mayalso comprise one or more other agents (e.g., prophylactic ortherapeutic agents that are currently being used, have been used, or areknown to be useful in the prevention, treatment or amelioration of aproliferative disorder or a symptom thereof).

The invention provides methods for preventing, managing, treating orameliorating a proliferative disorder, such as cancer, or one or moresymptoms thereof in a subject refractory (either completely orpartially) to existing agent therapies for such a proliferativedisorder, said methods comprising administering to said subject a doseof an effective amount of one or more compounds of the invention and adose of an effective amount of one or more therapies (e.g., one or moreprophylactic or therapeutic agents useful for the prevention, treatment,management, or amelioration of a proliferative disorder or a symptomthereof). The invention also provides methods for preventing, treating,managing, or ameliorating a proliferative disorder or a symptom thereofby administering one or more compounds of the invention in combinationwith any other therapy(ies) to patients who have proven refractory toother therapies but are no longer on these therapies.

The compounds of the invention and/or other therapies can beadministered to a subject by any route known to one of skill in the art.Examples of routes of administration include, but are not limited to,parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g.,inhalation), intranasal, transdermal (topical), transmucosal, and rectaladministration.

Agents Useful in Combination with Compounds of the Invention

Anticancer agents that can be co-administered with the compounds of theinvention include Taxol™, also referred to as “paclitaxel”, which is awell-known anti-cancer drug which acts by enhancing and stabilizingmicrotubule formation, and analogs of Taxol™, such as Taxotere™.Compounds that have the basic taxane skeleton as a common structurefeature, have also been shown to have the ability to arrest cells in theG2-M phases due to stabilized microtubules and may be useful fortreating cancer in combination with the compounds of the invention.

Other anti-cancer agents that can be employed in combination with thecompounds of the invention include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; interleukin II (includingrecombinant interleukin II, or rIL2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer drugs that can be employed in combination with thecompounds of the invention include: 20-epi-1,25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred anti-cancer drugs are 5-fluorouracil andleucovorin.

Other chemotherapeutic agents that can be employed in combination withthe compounds of the invention include but are not limited to alkylatingagents, antimetabolites, natural products, or hormones. Examples ofalkylating agents useful for the treatment or prevention of T-cellmalignancies in the methods and compositions of the invention includebut are not limited to, nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), ortriazenes (decarbazine, etc.). Examples of antimetabolites useful forthe treatment or prevention of T-cell malignancies in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).Examples of natural products useful for the treatment or prevention ofT-cell malignancies in the methods and compositions of the inventioninclude but are not limited to vinca alkaloids (e.g., vinblastin,vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase),or biological response modifiers (e.g., interferon alpha).

Examples of alkylating agents that can be employed in combination withthe compounds of the invention include but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesuseful for the treatment or prevention of cancer in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin). Examples of natural products useful for thetreatment or prevention of cancer in the methods and compositions of theinvention include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide,teniposide), antibiotics (e.g., actinomycin D, daunorubicin,doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha). Examples of hormones and antagonists useful for the treatment orprevention of cancer in the methods and compositions of the inventioninclude but are not limited to adrenocorticosteroids (e.g., prednisone),progestins (e.g., hydroxyprogesterone caproate, megestrol acetate,medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g.,testosterone propionate, fluoxymesterone), antiandrogen (e.g.,flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).Other agents that can be used in the methods and compositions of theinvention for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with the compounds of the invention include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCl), Resverastatin phosphatesodium, BPR-0Y-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Pharmaceutical Compositions

The present invention provides compositions for the treatment,prophylaxis, and amelioration of proliferative disorders, such ascancer. In a specific embodiment, a composition comprises one or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate or prodrug thereof. In another embodiment, acomposition of the invention comprises one or more prophylactic ortherapeutic agents other than a compound of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrugthereof. In another embodiment, a composition of the invention comprisesone or more compounds of the invention, or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate or prodrug thereof, and one or moreother prophylactic or therapeutic agents. In another embodiment, thecomposition comprises a compound of the invention, or a pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and apharmaceutically acceptable carrier, diluent or excipient.

In a preferred embodiment, a composition of the invention is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and dosage forms of the invention comprise one or moreactive ingredients in relative amounts and formulated in such a way thata given pharmaceutical composition or dosage form can be used to treator prevent proliferative disorders, such as cancer. Preferredpharmaceutical compositions and dosage forms comprise a compound offormulas (I) through (XIX), (IA) through (XIA), (XVIIA) through (XIXA),(IB) through (XIB), (XVIIB) through (XIXB), or Table 1, or apharmaceutically acceptable prodrug, salt, solvate, clathrate, hydrate,or prodrug thereof, optionally in combination with one or moreadditional active agents.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, oral (e.g., inhalation),intranasal, transdermal (topical), transmucosal, and rectaladministration. In a specific embodiment, the composition is formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous, subcutaneous, intramuscular, oral, intranasalor topical administration to human beings. In a preferred embodiment, apharmaceutical composition is formulated in accordance with routineprocedures for subcutaneous administration to human beings.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmocopia(USP) SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormulas (I) through (XIX), (IA) through (XIA), (XVIIA) through (XIXA),(IB) through (XIB), (XVIIB) through (XIXB), or Table 1, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof, in spheroids which further comprise microcrystallinecellulose and, optionally, hydroxypropylmethyl-cellulose coated with amixture of ethyl cellulose and hydroxypropylmethylcellulose. Suchextended release formulations can be prepared according to U.S. Pat. No.6,274,171, the entirely of which is incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of formulas (I) through (XIX),(IA) through (XIA), (XVIIA) through (XIXA), (IB) through (XIB), (XVIIB)through (XIXB), or Table 1, or a pharmaceutically acceptable salt,solvate, hydrate, clathrate, or prodrug thereof, by weight, about 50% toabout 94% microcrystalline cellulose, NF, by weight, and optionally fromabout 0.25% to about 1% by weight of hydroxypropyl-methylcellulose, USP,wherein the spheroids are coated with a film coating compositioncomprised of ethyl cellulose and hydroxypropylmethylcellulose.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays; aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Dosage & Frequency of Administration

The amount of the compound or composition of the invention which will beeffective in the prevention, treatment, management, or amelioration of aproliferative disorder, such as cancer, or one or more symptoms thereof,will vary with the nature and severity of the disease or condition, andthe route by which the active ingredient is administered. The frequencyand dosage will also vary according to factors specific for each patientdepending on the specific therapy (e.g., therapeutic or prophylacticagents) administered, the severity of the disorder, disease, orcondition, the route of administration, as well as age, body, weight,response, and the past medical history of the patient. Effective dosesmay be extrapolated from dose-response curves derived from in vitro oranimal model test systems. Suitable regiments can be selected by oneskilled in the art by considering such factors and by following, forexample, dosages reported in the literature and recommended in thePhysician's Desk Reference (57th ed., 2003).

Exemplary doses of a small molecule include milligram or microgramamounts of the small molecule per kilogram of subject or sample weight(e.g., about 1 microgram per kilogram to about 500 milligrams perkilogram, about 100 micrograms per kilogram to about 5 milligrams perkilogram, or about 1 microgram per kilogram to about 50 micrograms perkilogram).

In general, the recommended daily dose range of a compound of theinvention for the conditions described herein lie within the range offrom about 0.01 mg to about 1000 mg per day, given as a single onceevery one to four weeks, or once-a-day dose or as divided dosesthroughout a day. Specifically, a daily dose range should be from about5 mg to about 500 mg per day, more specifically, between about 10 mg andabout 200 mg per day. In managing the patient, the therapy should beinitiated at a lower dose, perhaps about 1 mg to about 25 mg, andincreased if necessary up to about 200 mg to about 1000 mg per day aseither a single dose or divided doses, depending on the patient's globalresponse. It may be necessary to use dosages of the active ingredientoutside the ranges disclosed herein in some cases, as will be apparentto those of ordinary skill in the art. Furthermore, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

Different therapeutically effective amounts may be applicable fordifferent proliferative disorders, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such proliferative disorders, butinsufficient to cause, or sufficient to reduce, adverse effectsassociated with the compounds of the invention are also encompassed bythe above described dosage amounts and dose frequency schedules.Further, when a patient is administered multiple dosages of a compoundof the invention, not all of the dosages need be the same. For example,the dosage administered to the patient may be increased to improve theprophylactic or therapeutic effect of the compound or it may bedecreased to reduce one or more side effects that a particular patientis experiencing.

In a specific embodiment, the dosage of the composition of the inventionor a compound of the invention administered to prevent, treat, manage,or ameliorate a proliferative disorders, such as cancer, or one or moresymptoms thereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's bodyweight. In another embodiment, the dosage of the composition of theinvention or a compound of the invention administered to prevent, treat,manage, or ameliorate a proliferative disorders, such as cancer, or oneor more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg,0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7m g, 0.25 mgto 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg,1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, 1 mg to 2.5 mg.

The dosages of prophylactic or therapeutic agents other than compoundsof the invention, which have been or are currently being used toprevent, treat, manage, or proliferative disorders, such as cancer, orone or more symptoms thereof can be used in the combination therapies ofthe invention. Preferably, dosages lower than those which have been orare currently being used to prevent, treat, manage, or ameliorate aproliferative disorder, or one or more symptoms thereof, are used in thecombination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorders, such as cancer, or one ormore symptoms thereof, can obtained from any reference in the artincluding, but not limited to, Hardman et al., eds., 1996, Goodman &Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9^(th) Ed,Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57^(th) Ed.,2003, Medical Economics Co., Inc., Montvale, N.J., which areincorporated herein by reference in its entirety.

In certain embodiments, when the compounds of the invention areadministered in combination with another therapy, the therapies (e.g.,prophylactic or therapeutic agents) are administered simultaneously,less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, atabout 1 hour apart, at about 1 to about 2 hours apart, at about 2 hoursto about 3 hours apart, at about 3 hours to about 4 hours apart, atabout 4 hours to about 5 hours apart, at about 5 hours to about 6 hoursapart, at about 6 hours to about 7 hours apart, at about 7 hours toabout 8 hours apart, at about 8 hours to about 9 hours apart, at about 9hours to about 10 hours apart, at about 10 hours to about 11 hoursapart, at about 11 hours to about 12 hours apart, at about 12 hours to18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart,36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84hours to 96 hours apart, or 96 hours to 120 hours part. In oneembodiment, two or more therapies (e.g., prophylactic or therapeuticagents) are administered within the same patent visit.

In certain embodiments, one or more compounds of the invention and oneor more other the therapies (e.g., prophylactic or therapeutic agents)are cyclically administered. Cycling therapy involves the administrationof a first therapy (e.g., a first prophylactic or therapeutic agents)for a period of time, followed by the administration of a second therapy(e.g., a second prophyladic or therapeutic agents) for a period of time,followed by the administration of a third therapy (e.g., a thirdprophylactic or therapeutic agents) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the agents, to avoidor reduce the side effects of one of the agents, and/or to improve theefficacy of the treatment.

In certain embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating a proliferative disorders, such ascancer, or one or more symptoms thereof, said methods comprisingadministering to a subject in need thereof a dose of at least 150 μg/kg,preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, atleast 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg,at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150mg/kg, or at least 200 mg/kg or more of one or more compounds of theinvention once every day, preferably, once every 2 days, once every 3days, once every 4 days, once every 5 days, once every 6 days, onceevery 7 days, once every 8 days, once every 10 days, once every twoweeks, once every three weeks, or once a month.

Other Embodiments

The compounds of the invention may be used as research tools (forexample, to evaluate the mechanism of action of new drug agents, toisolate new drug discovery targets using affinity chromatography, asantigens in an ELISA or ELISA-like assay, or as standards in in vitro orin vivo assays). These and other uses and embodiments of the compoundsand compositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES Experimental Rationale

Without wishing to be bound by theory, it is believed that the compoundsof this invention inhibit tubulin polymerization and, therefore, can beused to inhibit undesirable cellular proliferation in disorders such ascancer. The examples that follow demonstrate these properties.

Materials and General Methods

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMRspectra were recorded on a Varian 300 MHz NMR spectrometer. Significantpeaks are tabulated in the order: δ (ppm): chemical shift, multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (Hz) and number ofprotons.

Example 1 Synthesis of Representative Exemplary Compounds of thisInvention Compound 31-(3,4,5-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole

Step (a): Synthesis of 3,4,5-Trimethoxyphenyl azide

3,4,5-Trimethoxyaniline (1.83 g; 10 mmol) is added to a 100 mL flaskcontaining water (20 mL) and HCl (conc. aqueous solution, 5 mL). Thesolution is chilled to 0° C. and a solution of sodium nitrite (830 mg;12 mmol) in water (5 mL) is added. The solution is stirred at 0° C. for30 minutes, and then a solution of sodium azide (1.3 g; 20 mmol) inwater (5 mL) is added. After another 30 minutes of stirring,dichloromethane is added (20 mL) and the organic phase was collected andfiltered through a plug of silica, dried over magnesium sulfate and thesolvent was evaporated to give approximately two grams of3,4,5-trimethoxyphenyl azide.

¹H-NMR (CDCl₃)

(ppm) 6.21 (s, 2H); 3.82 (s, 6H); 3.80 (s, 3H)

Step (b): Synthesis of1-(3,4,5-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole

To a scintillation vial was added 4-ethynyl anisole (660 mg.; 5 mmol)and 3,4,5-trimethoxyphenyl azide (1.05 g.; 5 mmol) and the mixture washeated at 80° C. for 24 hours. The crude mixture was purified by columnchromatography to give1-(3,4,5-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole.

¹H-NMR (CDCl₃) δ (ppm) 7.80 (s, 1H); 7.19 (d, 2H); 6.88 (d, 2H); 6.58(s, 2H); 3.88 (s, 3H); 3.81 (s, 3H); 3.72 (s, 6H)

Expected MH+ mass ion=342, observed 342.1

Compound 51-(3,4,5-trimethoxy-phenyl)-5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole

To a scintillation vial was added (4-ethynyl phenyl)-dimethyl amine (6605 mmol) and 3,4,5-trimethoxyphenyl azide (1.05 g.; 5 mmol) and themixture was heated at 80° C. for 24 hours. The crude mixture waspurified by column chromatography to give1-(3,4,5-trimethoxy-phenyl)-5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole.

¹H-NMR (CDCl₃) δ (ppm) 7.78 (s, 1H); 7.11 (d; 2H); 6.64 (d, 2H); 6.62(s, 2H); 3.87 (s, 3H); 3.75 (s, 6H); 2.99 (s, 6H).

Compound 216PEG-2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate

A solution of1-(3,4,5-trimethoxy-phenyl)-5-(3-amino-4-methoxy-phenyl)-1H-[1,2,3]triazolehydrochloride (300 mg) and triethylamine (0.22 mL, 1.60 mmol) indichloromethane (3 mL) is added slowly to a solution of triphosgene (77mg, 0.26 mmol) in dichloromethane (5 mL) at 0° C. under nitrogenatmosphere. The reaction mixture is stirred for 30 min at roomtemperature, and then cooled to 0° C. before the addition of PEG (1.53g, 0.76 mmol) and triethylamine (0.12 mL, 0.77 mmol) in 2 ml ofdichloromethane. The resulting reaction mixture is stirred for 3 h. andwashed with NaHCO₃ solution. The aqueous layer is extracted withdichloromethane (2×), and the combined organic layers are washed withsaturated NaCl solution, dried over Na₂SO₄ and evaporated. The crudeproduct is purified by silica gel column chromatography (20% MeOH in EA)to give desired productPEG-2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate.

Synthesis of Amino-Acid Derivatives

tert-butyl2-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylamino)-2-oxoethylcarbamate(2)

To a solution of N-t-Boc-glycine (357 mg, 2 mmol) and N-methyl-imidazole(0.162 mL, 2 mmol) in THF (16 mL) cooled with ice methanesulfonylchloride (0.158 mL, 2 mmol) is added. Ice bath is removed, compound 1(0.4 g) is added as a solid, followed by thriethylamine (0.144 mL, 2.02mmol), and the reaction mixture is stirred at 40-50° C. overnight. Aresulted solution is decanted from a solid, a flask rinsed with EtOAc,and a combined organic solution is washed with saturated ammoniumchloride solution, then twice with water, brine and dried over anhydroussodium sulfate. The solution is filtered out through a celite pad,concentrated and the residue is dissolved in 2-propanol (3 mL) withheating, and hexane (1-2 mL) is added drop-wise to start precipitation.In 1 hour a solid is filtered out, washed with 1:1 Hexane:ether mixture(10 ml X₂) and vacuum-dried to give compound 2.

2-amino-N-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenyl)acetamidehydrochloride (3)

To a solution of 2 in THF (6 mL) a 1M solution of HCl in ethanol (17 mL)is added, and a resulted solution is stirred overnight at roomtemperature to form a suspension with product partly precipitated out.The reaction mixture is concentrated under reduced pressure keepingtemperature below 45° C. to ˜10 mL volume. A solid is filtered out,washed with ether (5 ml×2), hexane (5 mL) and vacuum-dried to givecompound 3.

Example 2 Cytotoxicity of Compounds of the Invention

The in vitro cytotoxicity of the compounds of the invention wasdetermined in the following human cell lines: HL-60, HL-60-TX1000 (MDR),MES-SA and MES-SA/DX5 (uterine sarcoma). MES-SA is a model of uterinesarcoma, and the cells are sensitive to a number of chemotherapeuticagents including doxorubicin, dactinomycin, mitomycin C, taxol andbleomycin. The MES-SA/Dx5 cell line was established in the presence ofincreasing concentrations of doxorubicin. The cells express high levelsof mdr-1 mRNA and p-glycoprotein and exhibit cross resistance to morethan fifteen chemotherapeutic agents including taxol, etoposide,mitomycin C, colchicine, vinblastine, dactinomycin, 5-fluorouracil,methotrexate and so on. All cells except HL-60-TX1000 were purchasedfrom ATCC. HL-60, a model of myeloid leukemia, was from ATCC andHL60/TX1000 was a gift from Dr. Bhalla of Emory University School ofMedicine. HL-60/TX1000 was isolated in vitro by subculturing HL-60 inprogressively higher concentration of Taxol. HL-60/TX1000 cellsover-express mdr-1 mRNA and p-glycoprotein, as determined by westernblot and immunofluorescence labeling with antiPGP antibodies

The cell lines were maintained in RPMI1640 (GIBCO) supplemented with 10%FCS, 100 units/mL penicillin, 100 ug/ml streptomycin, and 2 mML-glutamine. Cells were split every third day and diluted to aconcentration of 2×10⁵ cells/mL one day before the experiment wasperformed. All experiments were performed on exponentially growing cellcultures. Cell densities were 2.5×10⁴ cells/mL in all experiments.

Test compounds were prepared by dissolving the compounds at aconcentration of 10 mM in 100% DMSO. Final concentrations 10, 1, 0.1,0.01 and 0.001 μM were obtained by diluting the stock solution directlyinto the tissue culture medium. Cells were incubated with varyingconcentrations of test compounds for 72 hours and the IC₅₀ wasdetermined by MTS (i.e. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. IC₅₀ in this context stands for theconcentration of a compound required to inhibit 50% tumor cell growth.IC₅₀s of compounds 3 and 5 and Taxol are listed in Table 2 for each cellline. Surprisingly, Compounds 3 and 5 exhibited lower IC₅₀s formultidrug resistant cell lines HL-60-MDR and MES-SA/DX5 than fornon-multidrug resistant cell lines HL-60 and MES-SA. In contrast, Taxolexhibited an IC₅₀ of 2 nM against HL-60 cells and 5 nM against andMES-SA cells but has an IC₅₀ of 1,000 nM against multi-drug resistantcell line HL-60-TX1000 and 5,000 nM against multi-drug resistant cellline MES-SA/DX5.

Table 2: In Vitro Cytotoxicity of Compounds of the Invention.

TABLE 2 In vitro cytotoxicity of compounds of the invention. Cell LineCompound 3 Compound 5 Taxol HL-60 53 nM 41.5 nM    2 nM HL-60-TX1000 20nM  7.5 nM  1000 nM MES-SA 52 nM 68.5 nM    5 nM MES-SA/DX5 37 nM   29nM 5,000 nM

Example 3 Cell Cycle Analysis

MDA-435 cells are cultured in 6-well plates at 1×10⁶ cells/well and areuntreated (negative control), treated with Taxol (positive control), ortreated with a compound of the invention at 37° C. for 20 h. The cellsare detached with 1× trypsin and washed one time with PBS. Cycle TESTPLUS kit (BD PharMingen, Cat #340242) is used to stain the cells. Cellcycle is analyzed with FACScomp program (BS PharMingen).

Example 4 Inhibition of Tubulin Polymerization by Compounds of theInvention

Material and Methods: Wild-type Chinese Hamster Ovary cells (WT CHO)cells are maintained in Ham's F-12 medium supplemented with 10% fetalbovine serum (FBS; HyClone, Logan, Utah). Cells of low density (˜20%)growing on 2-well chambered cover-slips (Labtek (Campbell, Calif.) orFisher Scientific) are transfected with a mammalian expression vectorencoding α-tubulin-YFP (Clontech, Palo Alto, Calif.) with the use ofFuGENE 6 (Roche Molecular Biochemicals, Indianapolis, Ind.), accordingto the manufacturer's instructions. Twenty-four hours aftertransfection, the cells are cultured in 400 μg/ml G418 (Invitrogen,Carlsbad, Calif.)-containing selection medium for 2 weeks. Living cellsare examined using a fluorescent microscope for α-tubulin-YFPexpression. Cells in single colonies containing microtubules labeledwith α-tubulin-YFP are lifted and expanded in G418-containing medium.Expression of α-tubulin-YFP is confirmed by the presence of thetubulin-YFP labeled microtubule pattern identical to immunostainedmicrotubule pattern of non-transfected cells, as well as by subjectingthe cells to Western blot analysis using an anti-GFP antibody (RocheMolecular Biochemicals, Basel, Switzerland) and confirming the correctmass of the α-tubulin-YFP chimeric protein. Expressed tubulin-YFP isdetected as a single band in Western blots. The tubulin-YFP expressingcell lines (referred as CHO-α-tubulin-YFP cells) are used in the studiesdescribed below. Similar methods are used to generate MCF-7 cell linesstably expressing α-tubulin-YFP (referred as MCF7-α-tubulin-YFP cells).

CHO-α-tubulin-YFP or MCF7-α-tubulin-YFP cells are cultured in 2-wellchambered cover-slips (Labtek (Campbell, Calif.) or Fisher Scientific)for 24 hours before treatment with a compound of the invention. Forcomparison of the effects of treatment on α-tubulin-YFP labeledmicrotubules with the compounds of the invention, CHO-α-tubulin-YFP orMCF7-α-tubulin-YFP cells are treated with the a compound of theinvention, Taxol or equivalent concentrations of DMSO-containing mediafor various time periods before imaging. Tubulin-YFP fluorescence inliving cells or fixed cells is captured using a standard filter for FITCand objectives of 20× or 60× magnification on a Nikon TE300 microscopewith a Leica DC50 color digital camera (Leica, Bannockburn, Ill.) or aCoolSnap HQ monochrome CCD camera (Photonetrics, Tucson, Ariz.). TheLeica DC50 and CoolSnapHQ cameras are controlled with Leica DC50software and MetaVue/MetaMorph software, respectively (Universal ImagingCorp, Downingtown, Pa.). Inspection of the cells shows a typicalmicrotubule network in cells treated with DMSO alone, whereasmicrotubule bundle formation can be seen with Taxol, and a dispersepattern of cytoplasmic tubulin-YFP is expected with compounds of theinvention indicating microtubulin depolymerization.

Example 5 Microtubule Disruption in Cells Resistant to theDepolymerization Effects of Colchicine and Vincristine

The effects of compounds of the invention on microtubules can be studiedin CV-1 cells. The microtubules of CV-1 cells are known to be resistantto the depolymerizing effects of colchicine and vincristine. CV-1 cellsare treated with 500 nM of a compound of the invention, or vincristineor colchicines. At 24, 48 and 72 hr the cells are fixed and stained toexamine microtubule structure. In cells treated with compounds of theinvention, microtubule structures are expected to be diminished comparedto untreated cells. Disorganized but clear microtubule structures aretypically found in cells treated with either vincristine or colchicines.

Example 6 Anti-Tumor Activity Against Human Tumor Cells Line in NudeMouse Xenograft Models

The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, etal., Mol. Pathol. 55:294-299, 2002), is obtained from the American TypeCulture Collection (ATCC; Manassas, Va., USA). The human tumor cellline, RERF-LC-Al (RCB0444; S. Kyoizumi, et al., Cancer. Res.45:3274-3281, 1985), is obtained from the Riken Cell Bank (RCB; Tsukuba,Ibaraki, Japan). The cell lines are cultured in growth media preparedfrom 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media1640, 10% fetal bovine serum (FBS), 1% 100×L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10(6) cells that had been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 ml of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask is 90% confluent, typically in 5-7 days. To passageand expand the cell line, a 90% confluent flask is washed with 10 mL ofroom temperature phosphate buffered saline (PBS) and the cells aredisassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) and incubatingat 37° C. until the cells detached from the surface of the flask. Toinactivate the trypsin, 5 mL of growth media is added and then thecontents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 mL ofgrowth media and the cell number is determined using a hemocytometer.Approximately 1-3×10(6) cells per flask are seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reached 90% confluence, the above passagingprocess is repeated until sufficient cells are obtained for implantationinto mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 7 and 19 weeksof age at implantation. To implant MDA-MB-435S tumor cells into nudemice, the cells are trypsinized as above, washed in PBS and resuspendedat a concentration of 50×10(6) cells/mL in PBS. Using a 27 gauge needleand 1 cc syringe, 0.1 mL of the cell suspension is injected into thecorpus adiposum of nude mice. The corpus adiposum is a fat body locatedin the ventral abdominal vicera in the right quadrant of the abdomen atthe juncture of the os coxae (pelvic bone) and the os femoris (femur).To implant RERF-LC-Al tumor cells into nude mice, the cells aretrypsinized as above, washed in PBS and resuspended at a concentrationof 50×10(6) cells/mL in 50% non-supplemented RPMI Media 1640 and 50%Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford,Mass., USA). Using a 27 gauge needle and 1 cc syringe, 0.1 mL of thecell suspension is injected subcutaneously into the flank of nude mice.

Tumors are then permitted to develop in vivo until they reachedapproximately 100-200 mm³ in volume, which typically required 2-3 weeksfollowing implantation. Tumor volumes (V) are calculated by calipermeasurement of the width (W), length (L) and thickness (T) of tumorsusing the following formula: V=0.5326×(L×W×T). Animals were randomizedinto treatment groups so that the average tumor volumes of each groupwere similar at the start of dosing.

Stock solutions of test articles are prepared by dissolving theappropriate amounts of each compound in dimethyl sulfoxide (DMSO) bysonication in an ultrasonic water bath. Stock solutions are prepared atthe start of the study, stored at −20° C. and diluted fresh each day fordosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Ill.,USA) is also prepared by first heating 100% Cremophore RH40 at 50-60° C.until liquefied and clear, diluting 1:5 with 100% D5W, reheating againuntil clear and then mixing well. This solution is stored at roomtemperature for up to 3 months prior to use. To prepare formulations fordaily dosing, DMSO stock solutions are diluted 1:10 with 20% CremophoreRH40. The final formulation for dosing contained 10% DMSO, 18%Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amountof test article (e.g., a compound of the invention or a controlcompounds such as paclitaxel). Animals are intravenously (i.v.) injectedwith this solution at 10 ml per kg body weight on a schedule of 3 daysper week (Monday, Wednesday, Friday, with no dosing on Saturday andSunday) for a total of 9-10 doses.

Treatment with compounds of the invention at, for example, 6.25, 12.5and 25 mg/kg body weigh are expected to decreased the growth rate and/orcause tumor regression of MDA-MB-435S melanoma cells or of RERF-LC-Allung tumor cells in nude mice. Treatment with 7.5 mg/kg of paclitaxeltypically results in decreased tumor growth compared to animals treatedwith vehicle alone. Overt toxicity of Compound 3, as shown by theminimal effect on body weights, should be minimal with the compounds ofthe invention.

Example 7 Necrosis in a Nude Mouse Tumor Model

Mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), are obtainedfrom the American Type Culture Collection (ATCC; Manassas, Va., USA).The cell line is cultured in growth media prepared from 50% Dulbecco'sModified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetalbovine serum (FBS), 1% 100×L-glutamine, 1% 100× Penicillin-Streptomycin,1% 100× sodium pyruvate and 1% 100×MEM non-essential amino acids. FBS isobtained from ATCC and all other reagents are obtained from InvitrogenCorp. (Carlsbad, Calif., USA). Approximately 4-5×10(6) cells that havebeen cryopreserved in liquid nitrogen are rapidly thawed at 37° C. andtransferred to a 175 cm² tissue culture flask containing 50 ml of growthmedia and then incubated at 37° C. in a 5% CO₂ incubator. The growthmedia is replaced every 2-3 days until the flask became 90% confluent,typically in 5-7 days. To passage and expand the cell line, a 90%confluent flask is washed with 10 ml of room temperature phosphatebuffered saline (PBS) and the cells are disassociated by adding 5 ml 1×Trypsin-EDTA (Invitrogen) and incubating at 37° C. until the cellsdetached from the surface of the flask. To inactivate the trypsin, 5 mlof growth media is added and then the contents of the flask arecentrifuged to pellet the cells. The supernatant is aspirated and thecell pellet is resuspended in 10 ml of growth media and the cell numberdetermined using a hemocytometer. Approximately 1-3×10(6) cells perflask are seeded into 175 cm² flasks containing 50 ml of growth mediaand incubated at 37° C. in a 5% CO₂ incubator. When the flasks reach 90%confluence, the above passaging process is repeated until sufficientcells are obtained for implantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resuspended at aconcentration of 10×10(6) cells/ml in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 ml of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

Tumors are then permitted to develop in vivo until the majority reached75-125 mm³ in tumor volume, which typically required 1 week followingimplantation. Animals with oblong, very small or large tumors arediscarded, and only animals carrying tumors that display consistentgrowth rates are selected for studies. Tumor volumes (V) are calculatedby caliper measurement of the width (W), length (L) and thickness (T) oftumors using the following formula: V=0.5236×(L×W×T). Animals arerandomized into treatment groups so that each group has median tumorvolumes of ˜100 mm³ at the start of dosing.

To formulate compounds of the invention in DRD, a stock solution of thetest article is prepared by dissolving an appropriate amount of thecompound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonicwater bath. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5%dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) isalso prepared by first heating 100% Cremophore RH40 at 50-60° C. untilliquefied and clear, diluting 1:5 with 100% D5W, reheating again untilclear and then mixing well. This solution is stored at room temperaturefor up to 3 months prior to use. To prepare a DRD formulation fordosing, the DMSO stock solution is diluted 1:10 with 20% CremophoreRH40. The final DRD formulation for dosing contains 10% DMSO, 18%Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amountof test article.

Tumor-bearing animals are given a single intravenous (i.v.) bolusinjections of either DRD vehicle or a compound of the inventionformulated in DRD, both at 10 mL per kg body weight. Then, 4-24 hr afterdrug treatment, tumors are excised, cut in half and fixed overnight in10% neutral-buffered formalin. Each tumor is embedded in paraffin withthe cut surfaces placed downwards in the block, and rough cut until acomplete section is obtained. From each tumor, 5 μM serial sections areprepared and stained with hematoxylin and eosin. Slides are evaluatedmanually using light microscopy with a 10×10 square gridded reticle. Thepercentage of necrosis in a tumor is quantified at 200× magnification byscoring the total number of grid squares containing necrosis and thetotal number of grid squares containing viable tumor cells.

It is expected that compounds of the invention will rapidly increasecell necrosis after injection (e.g. single bolus injection of 25 mg/kgbody weight) relative to baseline necrosis observed in vehicle treatedtumors, as would be expected for a vascular targeting mechanism ofaction. Such rapid onset of necrosis is consistent with there being aloss of blood flow to tumors resulting in hypoxia and tumor cell death.

Example 8 Vascular Disrupting Activities in a Nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), isobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line is cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100×L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10⁶ cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 mL of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask becomes 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 mL of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detach from the surface of theflask. To inactivate the trypsin, 5 mL of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 mL ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10⁶ cells per flask are seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resuspended at aconcentration of 10×10⁶ cells/mL in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 mL of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

For the Evans Blue dye assay, tumors are permitted to develop in vivountil the majority reach 40-90 mm³ in tumor volume (to minimize theextent of tumor necrosis), which typically requires 4-6 days followingimplantation. Animals with visibly necrotic, oblong, very small or verylarge tumors are discarded and only animals carrying tumors that displayconsistent growth rates are selected for use. Tumor volumes (V) arecalculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals are randomized into treatment groups so that at the start ofdosing each group has median tumor volumes of ˜125 mm³ or ˜55 mm³ forEvans Blue dye assays.

To formulate compounds of the invention for dosing, the appropriateamount of compound is dissolved in 5% dextrose in water (D5W; AbbottLaboratories, North Chicago, Ill., USA). Vehicle-treated animals aredosed with D5W.

To conduct the Evans Blue dye assay, tumor-bearing animals are dosedwith vehicle or test article at 0 hr, and then i.v. injected with 100 μLof a 1% (w/v) Evan's Blue dye (Sigma #E-2129; St. Louis, Mo., USA)solution in 0.9% NaCl at +1 hr. Tumors are excised at +4 hr, weighed andthe tissue disassociated by incubation in 50 μL 1 N KOH at 60° C. for 16hr. To extract the dye, 125 μL of a 0.6 N phosphoric acid and 325 μLacetone is added, and the samples vigorously vortexed and thenmicrocentrifuged at 3000 RPM for 15 min to pellet cell debris. Theoptical absorbance of 200 μL of supernatant is then measured at 620 nMin a Triad spectrophotometer (Dynex Technologies, Chantilly, Va., USA).Background OD₆₂₀ values from similarly sized groups of vehicle or testarticle-treated animals that have not been injected with dye aresubtracted as background. OD₆₂₀ values are then normalized for tumorweight and dye uptake is calculated relative to vehicle-treated tumors.

To examine the vascular disrupting activity of compounds of theinvention, the Evans Blue dye assay is employed as a measurement oftumor blood volume (Graff et al., Eur J Cancer 36:1433-1440, 2000).Evans Blue dye makes a complex with serum albumin by electrostaticinteraction between the sulphonic acid group of the dye and the terminalcationic nitrogens of the lysine residues in albumin. The dye leaves thecirculation very slowly, principally by diffusion into extravasculartissues while still bound to albumin. Albumin-dye complex taken up bytumors is located in the extracellular space of non-necrotic tissue, andintracellular uptake and uptake in necrotic regions is negligible. Theamount of dye present in a tumor is a measurement of the tumor bloodvolume and microvessel permeability. Compounds of the invention areexpected to substantially decrease tumor dye uptake relative tovehicle-treated animals. Such a decrease in dye penetration into thetumor is consistent with there being a loss of blood flow to tumors dueto blockage of tumor vasculature, consistent with a vascular disruptingmechanism of action.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting in any way.

1-75. (canceled)
 76. A compound represented by formula (VII):

or a pharmaceutically acceptable salt thereof, wherein: one of R_(k) orR_(l) is —H and the other is

one of rings E or F is substituted with three or four substituents andthe other is substituted with one or more substituents; and with theproviso that when R_(k) is —H, then Ring E is not 4-aminophenyl.
 77. Thecompound of claim 76, wherein the compound is represented by structuralformula (III):

or a pharmaceutically acceptable salt thereof, wherein: one of R_(e) orR_(f) is —H and the other is

R₃, R₄, R₅, and R₆ are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionally,substituted alkynyl, an optionally-substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl,—C(O)R₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and R₇ and R₈, foreach occurrence, are, independently, —H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₉ is—H, halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; or R₆and R₉ together form —OCH₂O— or —OCH₂CH₂O—. R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; p is 1 or
 2. 78. The compound of claim 76, wherein thecompound is represented by structural formula (IX):

or a pharmaceutically acceptable salt thereof, wherein: one of R_(o) orR_(p) is —H and the other is

R₄, R₅, R₆, and R₁₇ are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and R₉ is —H, halo,an optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, aheteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; or R₆ and R₉ togetherform —OCH₂O— or —OCH₂CH₂O—; and The rest are the same as defined inclaim
 77. 79. The compound of claim 76, wherein the compound isrepresented by structural formula (X):

or a pharmaceutically acceptable salt thereof; wherein: one of R_(q) orR_(r) is —H and the other is

R₃, R₅, R₆, and R₁₈ are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and R₉ is —H, halo,an optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, aheteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; or R₆ and R₉ togetherform —OCH₂O— or —OCH₂CH₂O—; and The rest are the same as defined inclaim
 77. 80. The compound of claim 76, wherein the compound isrepresented by structural formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: one of R_(s) orR_(t) is —H and the other is

R₃, R₄, R₅, R₆, and R₁₈ are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇;—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and R₉ is —H, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; or R₆ and R₉ togetherform —OCH₂O— or —OCH₂CH₂O—; and The rest are the same as defined inclaim
 77. 81. A compound represented by structural formula (V):

or a pharmaceutically acceptable salt thereof, wherein: one of R_(i) orR_(j) is —H and the other is

R₆ is a halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ andR₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; R₉ is —H, halo, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, cyano,nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; or R₆ and R₉ togetherform —OCH₂O— or —OCH₂CH₂O—; R₁₀ and R₁₁, for each occurrence, areindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; or R₁₀ and R₁₁, taken togetherwith the nitrogen to which they are attached, form an optionallysubstituted heterocyclyl or an optionally substituted heteroaryl; andRing B is optionally substituted with one to three substituents; andRing C is optionally substituted with one or two substituents, p is 1 or2.
 81. The compound of claim 81, wherein the compound is represented byformula (IVA):

or a pharmaceutically acceptable salt thereof, wherein: one of R_(g) orR_(h) is —H and the other is

R^(x) is (R^(aa))_(m), —R^(aa)—C(O)(CH₂)_(n)C(O)OH,—C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or—(R^(aa))_(q)C(O)(Y₁); R^(y) is —H or lower alkyl; R^(w) is —H, analkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; R^(aa)is an amino acid residue or an amino acid residue analog; Y is CH₂, O,or NH; R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁; Alk is an optionallysubstituted alkylene; Het is an optionally substituted heteroalkyl; Y₁is a water soluble polymer with a molecular weight less than 60,000daltons; n is 1, 2, 3, or 4; m is an integer from 1 to 10; q is 0 or 1;Ring B is optionally substituted with one to three substituents; andRing C is optionally substituted with one or two substituents.
 82. Thecompound of claim 82, wherein the compound is represented by structuralformula (VA):

or a pharmaceutically acceptable salt thereof, wherein: one of R_(i) orR_(j) is —H and the other is

R₁₃ is —H, an alkyl, an alkoxy, a halo, nitro, cyano, —OH, —NH₂, analkyl amino, or a dialkyl amino.
 81. The compound of claim 81, whereinthe compound is represented by formula (IVB):

or a pharmaceutically acceptable salt thereof, wherein: one of R_(g) orR_(h) is —H and the other is

R^(w) is —H, an alkyl, an alkenyl, alkynyl, cyano, a haloalkyl, analkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; R₇, foreach occurrence, is independently —H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; Ring Bis optionally substituted with one to three substituents; and Ring C isoptionally substituted with one or two substituents.
 85. Apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a compound of claim 76 or 81.